Bicyclic heterocyclic compounds as protein tyrosine kinase inhibitors

ABSTRACT

The invention relates to new bicyclic heterocyclic derivative compounds of formula (I): wherein R 1 , q, A, B, X 1 , X 2 , X 3 , X 4 , X 5  and R 2  are as defined herein, to pharmaceutical compositions comprising said compounds and to the use of said compounds in the treatment of diseases, e.g. cancer.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a national phase filing under 35 U.S.C. §371 of PCTInternational Application No. PCT/GB2008/003439 filed Oct. 10, 2008, andpublished under PCT Article 21(2) in English as WO2009/047522 on Apr.16, 2009. PCT/GB2008/003439 claimed priority to U.S. Provisional PatentApplication No. 60/979,589, which was filed on Oct. 12, 2007; U.S.Provisional Patent Application No. 61/061,172, which was filed on Jun.13, 2008; and British Application No. 0720038.9, which was filed on Oct.12, 2007. The entire contents of each of the prior applications areincorporated herein by reference.

FIELD OF THE INVENTION

The invention relates to new bicyclic heterocyclic derivative compounds,to pharmaceutical compositions comprising said compounds and to the useof said compounds in the treatment of diseases, e.g. cancer.

SUMMARY OF THE INVENTION

According to a first aspect of the invention there is provided acompound of formula (I):

wherein

-   X₁, X₂ and X₃ are each independently selected from carbon or    nitrogen, such that at least one of X₁-X₃ represents nitrogen and    such that when X₁ represents nitrogen, at least one of X₂, X₃, X₄    and X₅ is nitrogen;-   X₄ represents CR³, nitrogen, NH or C═O;-   X₅ represents CR⁶, nitrogen, NH or C═O;-   provided that no more than three of X₁-X₅ represent nitrogen;-   represents a single or double bond, such that at least one bond    within the 5 membered ring system is a double bond and such that the    bond between X₄ and X₅ represents a single bond only when X₄ or X₅    represents C═O;-   R³ represents hydrogen, halogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆    alkynyl, C₁₋₆ alkoxy, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkenyl, cyano,    haloC₁₋₆ alkyl or haloC₁₋₆ alkoxy;-   A represents an aromatic or non-aromatic carbocyclic or heterocyclic    group which may be optionally substituted by one or more (e.g. 1, 2    or 3) R^(a) groups;-   B represents a —V-carbocyclic group or a —W-heterocyclyl group    wherein said carbocyclic and heterocyclyl groups may be optionally    substituted by one or more (e.g. 1, 2 or 3) R^(a) groups;-   R⁶ represents halogen, hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₂₋₆    alkenyl, C₂₋₆ alkynyl, —C≡N, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl,    —NHSO₂R^(w), —CH═N—OR^(w), or a 3-6 membered monocyclic heterocyclyl    group wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆    alkoxy and heterocyclyl groups may be optionally substituted by one    or more R^(a) groups;-   R^(e), R^(f) and R^(w) independently represent hydrogen or C₁₋₆    alkyl;-   R^(a) represents halogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,    C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, —OR^(x), —O—(CH₂)_(n)—OR^(x),    haloC₁₋₆ alkyl, haloC₁₋₆ alkoxy, C₁₋₆ alkanol, ═O, ═S, nitro,    Si(R^(x))₄, —(CH₂)_(s)—CN, —SO₂—R^(x), —COR^(x),    —(CR^(x)R^(y))_(s)—COOR^(z), —(CH₂)_(s)—CONR^(x)R^(y),    —(CH₂)_(s)—NR^(x)R^(y), —(CH₂)_(s)—NR^(x)COR^(y),    —(CH₂)_(s)—NR^(x)SO₂—R^(y), —(CH₂)_(s)—NH—SO₂—NR^(x)R^(y),    —OCONR^(x)R^(y), —(CH₂)_(s)—NR^(x)CO₂R^(y),    —O—(CH₂)_(s)—CR^(x)R^(y)—(CH₂)_(t)—OR^(z) or    —(CH₂)_(s)—SO₂NR^(x)R^(y) groups;-   R^(x), R^(y) and R^(z) independently represent hydrogen, C₁₋₆ alkyl,    C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkanol, hydroxy, C₁₋₆ alkoxy,    haloC₁₋₆ alkyl, —CO—(CH₂)_(n)—C₁₋₆ alkoxy, C₃₋₈ cycloalkyl or C₃₋₈    cycloalkenyl;-   R² represents a —CONR⁷R⁸, —COR^(x) or —COOR^(z) group;-   R⁷ and R⁸ independently represent hydrogen, C₁₋₆ alkyl, C₂₋₆    alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, aryl,    heterocyclyl or R⁷ and R⁸ together with the nitrogen atom to which    they are attached may form a nitrogen containing heterocyclyl ring,    wherein said C₁₋₆ alkyl, aryl and heterocyclyl may be optionally    substituted by one or more (e.g. 1, 2 or 3) R^(b) groups;-   R¹ and R^(b) independently represent an R^(a) group or a    —Y-carbocyclic or —Z-heterocyclyl group wherein said carbocyclic and    heterocyclyl groups may be optionally substituted by one or more    (e.g. 1, 2 or 3) R^(a) groups;-   V and W independently represent a bond or a —(CR^(e)R^(f))_(n)—    group;-   Y and Z independently represent a bond, —CO—(CH₂)_(s)—, —COO—,    —(CH₂)_(n)—, —NR^(x)—(CH₂)_(s)—, —(CH₂)_(s)—NR^(x)—, —CONR^(x)—,    —NR^(x)CO—, —SO₂NR^(x)—, —NR^(x)SO₂—, —NR^(x)CONR^(y)—,    —NR^(x)CSNR^(y)—, —O—(CH₂)_(s)—, —(CH₂)_(s)—O—, S—, —SO— or    —(CH₂)_(s)—SO₂—;-   n represents an integer from 1-4;-   s and t independently represent an integer from 0-4;-   q represents an integer from 0-2;-   or a pharmaceutically acceptable salt, solvate or derivative    thereof.

WO 01/38326 (Merck), WO 2003/048132 (Merck), WO 02/080914 (Gruenenthal),WO 01/14375 (Astra Zeneca), WO 2004/052286 (Merck), WO 00/53605 (Merck),WO 03/101993 (Neogenesis), WO 2005/075470 (SmithKline Beecham), WO2005/054230 (Cytopia), WO 2002/46168 (Astra Zeneca), WO 01/66098(Aventis), WO 97/12613 (Warner Lambert), WO 2006/094235 (SirtrisPharmaceuticals) and US 2006/0035921 (OSI Pharmaceuticals) each disclosea series of heterocyclic derivatives.

DETAILED DESCRIPTION OF THE INVENTION

According to a first aspect of the invention there is provided acompound of formula (I):

wherein

-   X₁, X₂ and X₃ are each independently selected from carbon or    nitrogen, such that at least one of X₁-X₃ represents nitrogen and    such that when X₁ represents nitrogen, at least one of X₂, X₃, X₄    and X₅ is nitrogen;-   X₄ represents CR³, nitrogen, NH or C═O;-   X₅ represents CR⁶, nitrogen, NH or C═O;-   provided that no more than three of X₁-X₅ represent nitrogen;-   represents a single or double bond, such that at least one bond    within the 5 membered ring system is a double bond and such that the    bond between X₄ and X₅ represents a single bond only when X₄ or X₅    represents C═O;-   R³ represents hydrogen, halogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆    alkynyl, C₁₋₆ alkoxy, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkenyl, cyano,    haloC₁₋₆ alkyl or haloC₁₋₆ alkoxy;-   A represents an aromatic or non-aromatic carbocyclic or heterocyclic    group which may be optionally substituted by one or more (e.g. 1, 2    or 3) R^(a) groups;-   B represents a —V-carbocyclic group or a —W-heterocyclyl group    wherein said carbocyclic and heterocyclyl groups may be optionally    substituted by one or more (e.g. 1, 2 or 3) R^(a) groups;-   R⁶ represents halogen, hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₂₋₆    alkenyl, C₂₋₆ alkynyl, —C≡N, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl,    —NHSO₂R^(w), —CH═N—OR^(w), or a 3-6 membered monocyclic heterocyclyl    group wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆    alkoxy and heterocyclyl groups may be optionally substituted by one    or more R^(a) groups;-   R^(e), R^(f) and R^(w) independently represent hydrogen or C₁₋₆    alkyl;-   R^(a) represents halogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,    C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, —OR^(x), —O—(CH₂)_(n)—OR^(x),    haloC₁₋₆ alkyl, haloC₁₋₆ alkoxy, C₁₋₆ alkanol, ═O, ═S, nitro,    Si(R^(x))₄, —(CH₂)_(s)—CN, —SO₂—R^(x), —COR^(x),    —(CR^(x)R^(y))_(s)—COOR^(z), —(CH₂)_(s)—CONR^(x)R^(y),    —(CH₂)_(s)—NR^(x)R^(y), —(CH₂)_(s)—NR^(x)COR^(y),    —(CH₂)_(s)—NR^(x)SO₂—R^(y), —(CH₂)_(s)—NH—SO₂—NR^(x)R^(y),    —OCONR^(x)R^(y), —(CH₂)_(s)—NR^(x)CO₂R^(y),    —O—(CH₂)_(s)—CR^(x)R^(y)—(CH₂)_(t)—OR^(z) or    —(CH₂)_(s)—SO₂NR^(x)R^(y) groups;-   R^(x), R^(y) and R^(z) independently represent hydrogen, C₁₋₆ alkyl,    C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkanol, hydroxy, C₁₋₆ alkoxy,    haloC₁₋₆ alkyl, —CO—(CH₂)_(n)—C₁₋₆ alkoxy, C₃₋₈ cycloalkyl or C₃₋₈    cycloalkenyl;-   R² represents a —CONR⁷R⁸, —COR^(x) or —COOR^(z) group;-   R⁷ and R⁸ independently represent hydrogen, C₁₋₆ alkyl, C₂₋₆    alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, aryl,    heterocyclyl or R⁷ and R⁸ together with the nitrogen atom to which    they are attached may form a nitrogen containing heterocyclyl ring,    wherein said C₁₋₆ alkyl, aryl and heterocyclyl may be optionally    substituted by one or more (e.g. 1, 2 or 3) R^(b) groups;-   R¹ and R^(b) independently represent an R^(a) group or a    —Y-carbocyclic or —Z-heterocyclyl group wherein said carbocyclic and    heterocyclyl groups may be optionally substituted by one or more    (e.g. 1, 2 or 3) R^(a) groups;-   V and W independently represent a bond or a —(CR^(e)R^(f))_(n)—    group;-   Y and Z independently represent a bond, —CO—(CH₂)_(s)—, —COO—,    —(CH₂)_(n)—, —NR^(x)—(CH₂)_(s)—, —(CH₂)_(s)—NR^(x)—, —CONR^(x)—,    —NR^(x)CO—, —SO₂NR^(x)—, —NR^(x)SO₂—, —NR^(x)CONR^(y)—,    —NR^(x)CSNR^(y)—, —O—(CH₂)_(s)—, —(CH₂)_(s)—O—, S—, —SO— or    —(CH₂)_(s)—SO₂—;-   n represents an integer from 1-4;-   s and t independently represent an integer from 0-4;-   q represents an integer from 0-2;-   or a pharmaceutically acceptable salt, solvate or derivative    thereof.

According to one particular aspect of the invention there is provided acompound of formula (Ia):

wherein

-   X₁, X₂ and X₃ are each independently selected from carbon or    nitrogen, such that at least one of X₁-X₃ represents nitrogen;-   X₄ represents CR³ or nitrogen;-   X₅ represents CR⁶, nitrogen or C═O;-   provided that no more than three of X₁-X₅ represent nitrogen;-   represents a single or double bond, such that when X₅ represents    C═O, X₄ and X₅ are joined by a single bond and such that at least    one bond within the 5 membered ring system is a double bond;-   R³ represents hydrogen, halogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆    alkynyl, C₁₋₆ alkoxy, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkenyl, cyano,    haloC₁₋₆ alkyl, haloC₁₋₆ alkoxy or ═O;-   A represents an aromatic or non-aromatic carbocyclic or heterocyclic    group which may be optionally substituted by one or more (e.g. 1, 2    or 3) R^(a) groups;-   B represents a —V-carbocyclic group or a —W-heterocyclyl group    wherein said carbocyclic and heterocyclyl groups may be optionally    substituted by one or more (e.g. 1, 2 or 3) R^(a) groups;-   R⁶ represents halogen, hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₂₋₆    alkenyl, C₂₋₆ alkynyl, —C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl,    —NHSO₂R^(w), —CH═N—OR^(w), or a 3-6 membered monocyclic heterocyclyl    group wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆    alkoxy and heterocyclyl groups may be optionally substituted by one    or more R^(a) groups;-   R^(e), R^(f) and R^(w) independently represent hydrogen or C₁₋₆    alkyl;-   R^(a) represents halogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,    C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, —OR^(x), —O—(CH₂)_(n)—OR^(x),    haloC₁₋₆ alkyl, haloC₁₋₆ alkoxy, C₁₋₆ alkanol, ═O, ═S, nitro,    Si(R^(x))₄, —(CH₂)_(s)—CN, —SO—R^(x), —SO₂—R^(x), —COR^(x),    —(CR^(x)R^(y))_(s)—COOR^(z), —(CH₂)_(s)—CONR^(x)R^(y),    —(CH₂)_(s)—NR^(x)R^(y), —(CH₂)_(s)—NR^(x)COR^(y),    —(CH₂)_(s)—NR^(x)SO₂—R^(y), —(CH₂)_(s)—NH—SO₂—NR^(x)R^(y),    —OCONR^(x)R^(y), —(CH₂)_(s)—NR^(x)CO₂R^(y),    —O—(CH₂)_(s)—CR^(x)R^(y)—(CH₂)_(t)—OR^(z) or    —(CH₂)_(s)—SO₂NR^(x)R^(y) groups;-   R^(x), R^(y) and R^(z) independently represent hydrogen, C₁₋₆ alkyl,    C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkanol, hydroxy, C₁₋₆ alkoxy,    haloC₁₋₆ alkyl, —CO—(CH₂)_(n)—C₁₋₆ alkoxy, C₃₋₈ cycloalkyl or C₃₋₈    cycloalkenyl;-   R² represents a —CONR⁷R⁸, —COR^(x) or —COOR^(z) group;-   R⁷ and R⁸ independently represent hydrogen, C₁₋₆ alkyl, C₂₋₆    alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, aryl,    heterocyclyl or R⁷ and R⁸ together with the nitrogen atom to which    they are attached may form a nitrogen containing heterocyclyl ring,    wherein said alkyl, aryl and heterocyclyl may be optionally    substituted by one or more (e.g. 1, 2 or 3) R^(b) groups;-   R¹ and R^(b) independently represent an R^(a) group or a —Y-aryl or    —Z-heterocyclyl group wherein said aryl and heterocyclyl groups may    be optionally substituted by one or more (e.g. 1, 2 or 3) R^(a)    groups;-   V and W independently represent a bond or a —(CR^(e)R^(f))_(n)—    group;-   Y and Z independently represent a bond, —CO—(CH₂)_(s)—, —COO—,    —(CH₂)_(n)—, —NR^(x)—(CH₂)_(n)—, —(CH₂)_(n)—NR^(x)—, —CONR^(x)—,    —NR^(x)CO—, —SO₂NR^(x)—, —NR^(x)SO₂—, —NR^(x)CONR^(y)—,    —NR^(x)CSNR^(y)—, —O—(CH₂)_(s)—, —(CH₂)_(s)—O—, S—, —SO— or    —(CH₂)_(s)—SO₂—;-   n represents an integer from 1-4;-   s and t independently represent an integer from 0-4;-   q represents an integer from 0-2;-   aryl represents a carbocyclic ring;-   heterocyclyl represents a heterocyclic ring;-   or a pharmaceutically acceptable salt, solvate or derivative    thereof.

According to a further particular aspect of the invention there isprovided a compound of formula (Ib):

wherein

-   X₁, X₂ and X₃ are each independently selected from carbon or    nitrogen, such that at least one of X₁-X₃ represents nitrogen and    such that when X₁ represents nitrogen, at least one of X₂, X₃, X₄    and X₅ is nitrogen;-   X₄ represents CR³ or nitrogen;-   X₅ represents CR⁶, nitrogen or C═O;-   provided that no more than three of X₁-X₅ represent nitrogen;-   represents a single or double bond, such that at least one bond    within the 5 membered ring system is a double bond;-   R³ represents hydrogen, halogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆    alkynyl, C₁₋₆ alkoxy, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkenyl, cyano,    haloC₁₋₆ alkyl, haloC₁₋₆ alkoxy or ═O;-   A represents an aromatic or non-aromatic carbocyclic or heterocyclic    group which may be optionally substituted by one or more (e.g. 1, 2    or 3) R^(a) groups;-   B represents a —V-carbocyclic group or a —W-heterocyclyl group    wherein said carbocyclic and heterocyclyl groups may be optionally    substituted by one or more (e.g. 1, 2 or 3) R^(a) groups;-   R⁶ represents halogen, hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₂₋₆    alkenyl, C₂₋₆ alkynyl, —C≡N, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl,    —NHSO₂R^(w), —CH═N—OR^(w), or a 3-6 membered monocyclic heterocyclyl    group wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆    alkoxy and heterocyclyl groups may be optionally substituted by one    or more R^(a) groups;-   R^(e), R^(f) and R^(w) independently represent hydrogen or C₁₋₆    alkyl;-   R^(a) represents halogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,    C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, —OR^(x), —O—(CH₂)_(n)—OR^(x),    haloC₁₋₆ alkyl, haloC₁₋₆ alkoxy, C₁₋₆ alkanol, ═O, ═S, nitro,    Si(R^(x))₄, —(CH₂)_(s)—CN, —S—R^(x), —SO—R^(x), —SO₂—R^(x),    —COR^(x), —(CR^(x)R^(y))_(s)—COOR^(z), —(CH₂)_(s)—CONR^(x)R^(y),    —(CH₂)_(s)—NR^(x)R^(y), —(CH₂)_(s)—NR^(x)COR^(y),    —(CH₂)_(s)—NR^(x)SO₂—R^(y), —(CH₂)_(s)—NH—SO₂—NR^(x)R^(y),    —OCONR^(x)R^(y)—(CH₂)_(s)—NR^(x)CO₂R^(y),    —O—(CH₂)_(s)—CR^(x)R^(y)—(CH₂)_(t)—OR^(z) or    —(CH₂)_(s)—SO₂NR^(x)R^(y) groups;-   R^(x), R^(y) and R^(z) independently represent hydrogen, C₁₋₆ alkyl,    C₂₋₆ alkenyl, C₂₋₆ alkynyl,-   C₁₋₆ alkanol, hydroxy, C₁₋₆ alkoxy, haloC₁₋₆ alkyl,    —CO—(CH₂)_(n)—C₁₋₆ alkoxy, C₃₋₈ cycloalkyl or C₃₋₈ cycloalkenyl;-   R² represents a —CONR⁷R⁸, —COR^(x) or —COOR^(z) group;-   R⁷ and R⁸ independently represent hydrogen, C₁₋₆ alkyl, C₂₋₆    alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, aryl,    heterocyclyl or R⁷ and R⁸ together with the nitrogen atom to which    they are attached may form a nitrogen containing heterocyclyl ring,    wherein said alkyl, aryl and heterocyclyl may be optionally    substituted by one or more (e.g. 1, 2 or 3) R^(b) groups;-   R¹ and R^(b) independently represent an R^(a) group or a    —Y-carbocyclic or —Z-heterocyclyl group wherein said carbocyclic and    heterocyclyl groups may be optionally substituted by one or more    (e.g. 1, 2 or 3) R^(a) groups;-   V and W independently represent a bond or a —(CR^(e)R^(f))_(n)—    group;-   Y and Z independently represent a bond, —CO—(CH₂)_(s)—, —COO—,    —(CH₂)_(n)—, —NR^(x)—(CH₂)_(n)—, —(CH₂)_(n)—NR^(x)—, —CONR^(x)—,    —NR^(x)CO—, —SO₂NR^(x)—, —NR^(x)SO₂—, —NR^(x)CONR^(y)—,    —NR^(x)CSNR^(y)—, —O—(CH₂)_(s)—, —(CH₂)_(s)—O—, S—, —SO— or    —(CH₂)_(s)—SO₂—;-   n represents an integer from 1-4;-   s and t independently represent an integer from 0-4;-   q represents an integer from 0-2;-   or a pharmaceutically acceptable salt, solvate or derivative    thereof.

The term ‘C₁₋₆ alkyl’ as used herein as a group or a part of the grouprefers to a linear or branched saturated hydrocarbon group containingfrom 1 to 6 carbon atoms. Examples of such groups include methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert butyl, n-pentyl,isopentyl, neopentyl or hexyl and the like.

The term ‘C₂₋₆ alkenyl’ as used herein as a group or a part of the grouprefers to a linear or branched hydrocarbon group containing a C═C bond.

The term ‘C₁₋₆ alkoxy’ as used herein refers to an —O—C₁₋₆ alkyl groupwherein C₁₋₆ alkyl is as defined herein. Examples of such groups includemethoxy, ethoxy, propoxy, butoxy, pentoxy or hexoxy and the like.

The term ‘C₁₋₆ alkanol’ as used herein refers to a C₁₋₆ alkyl groupsubstituted by one or more hydroxy groups, wherein C₁₋₆ alkyl is asdefined herein. Examples of such groups include hydroxymethyl,hydroxyethyl, hydroxypropyl and the like.

The term ‘C₃₋₈ cycloalkyl’ as used herein refers to a saturatedmonocyclic hydrocarbon ring of 3 to 8 carbon atoms. Examples of suchgroups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl or cyclooctyl and the like.

The term ‘C₃₋₆ cycloalkyl’ as used herein refers to a saturatedmonocyclic hydrocarbon ring of 3 to 6 carbon atoms. Examples of suchgroups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and thelike.

The term ‘halogen’ as used herein refers to a fluorine, chlorine,bromine or iodine atom.

The term ‘haloC₁₋₆ alkyl’ as used herein refers to a C₁₋₆ alkyl group asdefined herein wherein at least one hydrogen atom is replaced withhalogen. Examples of such groups include fluoroethyl, trifluoromethyl ortrifluoroethyl and the like.

The term ‘haloC₁₋₆ alkoxy’ as used herein refers to a C₁₋₆ alkoxy groupas herein defined wherein at least one hydrogen atom is replaced withhalogen. Examples of such groups include difluoromethoxy ortrifluoromethoxy and the like.

References to “carbocyclic” and “heterocyclic” groups as used hereinshall, unless the context indicates otherwise, include both aromatic andnon-aromatic ring systems. Thus, for example, the term “carbocyclic andheterocyclic groups” includes within its scope aromatic, non-aromatic,unsaturated, partially saturated and fully saturated carbocyclic andheterocyclic ring systems. In general, such groups may be monocyclic orbicyclic and may contain, for example, 3 to 12 ring members, moreusually 5 to 10 ring members. Examples of monocyclic groups are groupscontaining 3, 4, 5, 6, 7, and 8 ring members, more usually 3 to 7, andpreferably 5 or 6 ring members. Examples of bicyclic groups are thosecontaining 8, 9, 10, 11 and 12 ring members, and more usually 9 or 10ring members. Where reference is made herein to carbocyclic andheterocyclic groups, the carbocyclic or heterocyclic ring can, unlessthe context indicates otherwise, be unsubstituted or substituted by oneor more substituents for example molecular fragments, molecularscaffolds or functional groups as discussed herein. It will beappreciated that references to “carbocyclic” and “heterocyclic” groupsinclude reference to carbocyclic and heterocyclic groups which may beoptionally substituted by one or more (e.g. 1, 2 or 3) R^(a) or R^(b)groups.

The carbocyclic or heterocyclic groups can be aryl or heteroaryl groupshaving from 5 to 12 ring members, more usually from 5 to 10 ringmembers. The term “aryl” as used herein refers to a carbocyclic grouphaving aromatic character and the term “heteroaryl” is used herein todenote a heterocyclic group having aromatic character. The terms “aryl”and “heteroaryl” embrace polycyclic (e.g. bicyclic) ring systems whereinone or more rings are non-aromatic, provided that at least one ring isaromatic. In such polycyclic systems, the group may be attached by thearomatic ring, or by a non-aromatic ring. It will be appreciated thatthe term “aryl” has the definition as defined herein except forcompounds of formula (Ia), (Ic) and (Id) wherein aryl represents acarbocyclic ring as defined herein. In one embodiment of compounds offormula (Ia), (Ic) and (Id), aryl represents an aromatic ring.

The term “non-aromatic group” embraces unsaturated ring systems withoutaromatic character, partially saturated and fully saturated carbocyclicand heterocyclic ring systems. The terms “unsaturated” and “partiallysaturated” refer to rings wherein the ring structure(s) contains atomssharing more than one valence bond i.e. the ring contains at least onemultiple bond e.g. a C═C, C≡C or N═C bond. The term “fully saturated”refers to rings where there are no multiple bonds between ring atoms.Saturated carbocyclic groups include cycloalkyl groups as defined below.Partially saturated carbocyclic groups include cycloalkenyl groups asdefined below, for example cyclopentenyl, cyclohexenyl, cycloheptenyland cyclooctenyl. Saturated heterocyclic groups include piperidine,morpholine, thiomorpholine. Partially saturated heterocyclic groupsinclude pyrazolines, for example 2-pyrazoline and 3-pyrazoline.

Examples of heteroaryl groups are monocyclic and bicyclic groupscontaining from five to twelve ring members, and more usually from fiveto ten ring members. The heteroaryl group can be, for example, a fivemembered or six membered monocyclic ring or a bicyclic structure formedfrom fused five and six membered rings or two fused six membered rings,or two fused five membered rings. Each ring may contain up to about fiveheteroatoms typically selected from nitrogen, sulphur and oxygen.Typically the heteroaryl ring will contain up to 4 heteroatoms, moretypically up to 3 heteroatoms, more usually up to 2, for example asingle heteroatom. In one embodiment, the heteroaryl ring contains atleast one ring nitrogen atom. The nitrogen atoms in the heteroaryl ringscan be basic, as in the case of an imidazole or pyridine, or essentiallynon-basic as in the case of an indole or pyrrole nitrogen. In generalthe number of basic nitrogen atoms present in the heteroaryl group,including any amino group substituents of the ring, will be less thanfive.

Examples of five membered heteroaryl groups include but are not limitedto pyrrole, furan, thiophene, imidazole, furazan, oxazole, oxadiazole,oxatriazole, isoxazole, thiazole, thiadiazole, isothiazole, pyrazole,triazole and tetrazole groups.

Examples of six membered heteroaryl groups include but are not limitedto pyridine, pyrazine, pyridazine, pyrimidine and triazine.

A bicyclic heteroaryl group may be, for example, a group selected from:

-   -   a) a benzene ring fused to a 5- or 6-membered ring containing 1,        2 or 3 ring heteroatoms;    -   b) a pyridine ring fused to a 5- or 6-membered ring containing        1, 2 or 3 ring heteroatoms;    -   c) a pyrimidine ring fused to a 5- or 6-membered ring containing        1 or 2 ring heteroatoms;    -   d) a pyrrole ring fused to a 5- or 6-membered ring containing 1,        2 or 3 ring heteroatoms;    -   e) a pyrazole ring fused to a 5- or 6-membered ring containing 1        or 2 ring heteroatoms;    -   f) an imidazole ring fused to a 5- or 6-membered ring containing        1 or 2 ring heteroatoms;    -   g) an oxazole ring fused to a 5- or 6-membered ring containing 1        or 2 ring heteroatoms;    -   h) an isoxazole ring fused to a 5- or 6-membered ring containing        1 or 2 ring heteroatoms;    -   i) a thiazole ring fused to a 5- or 6-membered ring containing 1        or 2 ring heteroatoms;    -   j) an isothiazole ring fused to a 5- or 6-membered ring        containing 1 or 2 ring heteroatoms;    -   k) a thiophene ring fused to a 5- or 6-membered ring containing        1, 2 or 3 ring heteroatoms;    -   l) a furan ring fused to a 5- or 6-membered ring containing 1, 2        or 3 ring heteroatoms;    -   m) a cyclohexyl ring fused to a 5- or 6-membered ring containing        1, 2 or 3 ring heteroatoms; and    -   n) a cyclopentyl ring fused to a 5- or 6-membered ring        containing 1, 2 or 3 ring heteroatoms.

Particular examples of bicyclic heteroaryl groups containing a fivemembered ring fused to another five membered ring include but are notlimited to imidazothiazole (e.g. imidazo[2,1-b]thiazole) andimidazoimidazole (e.g. imidazo[1,2-a]imidazole).

Particular examples of bicyclic heteroaryl groups containing a sixmembered ring fused to a five membered ring include but are not limitedto benzofuran, benzothiophene, benzimidazole, benzoxazole,isobenzoxazole, benzisoxazole, benzthiazole, benzisothiazole,isobenzofuran, indole, isoindole, indolizine, indoline, isoindoline,purine (e.g., adenine, guanine), indazole, pyrazolopyrimidine (e.g.pyrazolo[1,5-a]pyrimidine), triazolopyrimidine (e.g.[1,2,4]triazolo[1,5-a]pyrimidine), benzodioxole, imidazopyridine andpyrazolopyridine (e.g. pyrazolo[1,5-a]pyridine) groups.

Particular examples of bicyclic heteroaryl groups containing two fusedsix membered rings include but are not limited to quinoline,isoquinoline, chroman, thiochroman, chromene, isochromene, chroman,isochroman, benzodioxan, quinolizine, benzoxazine, benzodiazine,pyridopyridine, quinoxaline, quinazoline, cinnoline, phthalazine,naphthyridine and pteridine groups.

Examples of polycyclic aryl and heteroaryl groups containing an aromaticring and a non-aromatic ring include tetrahydronaphthalene,tetrahydroisoquinoline, tetrahydroquinoline, dihydrobenzthiene,dihydrobenzfuran, 2,3-dihydrobenzo [1,4]dioxine, benzo[1,3]dioxole,4,5,6,7-tetrahydrobenzofuran, tetrahydrotriazolopyrazine (e.g.5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine), indoline and indanegroups.

A nitrogen-containing heteroaryl ring must contain at least one ringnitrogen atom. Each ring may, in addition, contain up to about fourother heteroatoms typically selected from nitrogen, sulphur and oxygen.Typically the heteroaryl ring will contain up to 3 heteroatoms, forexample 1, 2 or 3, more usually up to 2 nitrogens, for example a singlenitrogen. The nitrogen atoms in the heteroaryl rings can be basic, as inthe case of an imidazole or pyridine, or essentially non-basic as in thecase of an indole or pyrrole nitrogen. In general the number of basicnitrogen atoms present in the heteroaryl group, including any aminogroup substituents of the ring, will be less than five.

Examples of nitrogen-containing heteroaryl groups include, but are notlimited to, pyridyl, pyrrolyl, imidazolyl, oxazolyl, oxadiazolyl,thiadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl,furazanyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl,triazolyl (e.g., 1,2,3-triazolyl, 1,2,4-triazolyl), tetrazolyl,quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzisoxazole,benzthiazolyl and benzisothiazole, indolyl, 3H-indolyl, isoindolyl,indolizinyl, isoindolinyl, purinyl (e.g., adenine [6-aminopurine],guanine [2-amino-6-hydroxypurine]), indazolyl, quinolizinyl,benzoxazinyl, benzodiazinyl, pyridopyridinyl, quinoxalinyl,quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl and pteridinyl.

Examples of nitrogen-containing polycyclic heteroaryl groups containingan aromatic ring and a non-aromatic ring includetetrahydroisoquinolinyl, tetrahydroquinolinyl, and indolinyl.

Examples of carbocyclic aryl groups include phenyl, naphthyl, indenyl,and tetrahydronaphthyl groups.

Examples of non-aromatic heterocyclic groups are groups having from 3 to12 ring members, more usually 5 to 10 ring members. Such groups can bemonocyclic or bicyclic, for example, and typically have from 1 to 5heteroatom ring members (more usually 1, 2, 3 or 4 heteroatom ringmembers), usually selected from nitrogen, oxygen and sulphur. Theheterocyclic groups can contain, for example, cyclic ether moieties(e.g. as in tetrahydrofuran and dioxane), cyclic thioether moieties(e.g. as in tetrahydrothiophene and dithiane), cyclic amine moieties(e.g. as in pyrrolidine), cyclic amide moieties (e.g. as inpyrrolidone), cyclic thioamides, cyclic thioesters, cyclic ureas (e.g.as in imidazolidin-2-one) cyclic ester moieties (e.g. as inbutyrolactone), cyclic sulphones (e.g. as in sulpholane and sulpholene),cyclic sulphoxides, cyclic sulphonamides and combinations thereof (e.g.thiomorpholine).

Particular examples include morpholine, piperidine (e.g. 1-piperidinyl,2-piperidinyl, 3-piperidinyl and 4-piperidinyl), piperidone, pyrrolidine(e.g. 1-pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl), pyrrolidone,azetidine, pyran (2H-pyran or 4H-pyran), dihydrothiophene, dihydropyran,dihydrofuran, dihydrothiazole, tetrahydrofuran, tetrahydrothiophene,dioxane, tetrahydropyran (e.g. 4-tetrahydro pyranyl), imidazoline,imidazolidinone, oxazoline, thiazoline, 2-pyrazoline, pyrazolidine,piperazone, piperazine, and N-alkyl piperazines such as N-methylpiperazine. In general, preferred non-aromatic heterocyclic groupsinclude saturated groups such as piperidine, pyrrolidine, azetidine,morpholine, piperazine and N-alkyl piperazines.

In a nitrogen-containing non-aromatic heterocyclic ring the ring mustcontain at least one ring nitrogen atom. The heterocylic groups cancontain, for example cyclic amine moieties (e.g. as in pyrrolidine),cyclic amides (such as a pyrrolidinone, piperidone or caprolactam),cyclic sulphonamides (such as an isothiazolidine 1,1-dioxide,[1,2]thiazinane 1,1-dioxide or [1,2]thiazepane 1,1-dioxide) andcombinations thereof. Particular examples of nitrogen-containingnon-aromatic heterocyclic groups include aziridine, morpholine,thiomorpholine, piperidine (e.g. 1-piperidinyl, 2-piperidinyl,3-piperidinyl and 4-piperidinyl), pyrrolidine (e.g. 1-pyrrolidinyl,2-pyrrolidinyl and 3-pyrrolidinyl), pyrrolidone, dihydrothiazole,imidazoline, imidazolidinone, oxazoline, thiazoline,6H-1,2,5-thiadiazine, 2-pyrazoline, 3-pyrazoline, pyrazolidine,piperazine, and N-alkyl piperazines such as N-methyl piperazine.

The carbocyclic and heterocyclic groups can be polycyclic fused ringsystems or bridged ring systems such as bicycloalkanes, tricycloalkanesand their oxa- and aza analogues (e.g. adamantane and oxa-adamantane).For an explanation of the distinction between fused and bridged ringsystems, see Advanced Organic Chemistry, by Jerry March, 4^(th) Edition,Wiley Interscience, pages 131-133, 1992.

Examples of non-aromatic carbocyclic groups include cycloalkane groupssuch as cyclohexyl and cyclopentyl, cycloalkenyl groups such ascyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl, as well ascyclohexadienyl, cyclooctatetraene, tetrahydronaphthenyl and decalinyl.

The heterocyclic groups can each be unsubstituted or substituted by oneor more substituent groups. For example, heterocyclic groups can beunsubstituted or substituted by 1, 2, 3 or 4 substituents. Where theheterocyclic group is monocyclic or bicyclic, typically it isunsubstituted or has 1, 2 or 3 substituents.

Examples of ring systems encompassed by the definitions of X₁-X₅ areshown in the following formulae (a)-(p) and (r)-(t):

Further examples of ring systems encompassed by the definitions of X₁-X₅are shown in the following formulae (u)-(v):

As mentioned above,

represents a single or double bond. It will be clear to the skilledperson that when X₄ or X₅ represents C═O, X₄ and X₅ are joined by asingle bond. In one embodiment X₄ and X₅ are joined by a double bond.

In one embodiment, two bonds within the 5 membered ring system aredouble bonds.

In one embodiment, X₁ represents C.

In one embodiment, X₁ and X₃ represent C, X₅ represents CH and X₂ and X₄represent nitrogen (i.e. a ring system of formula (a)).

In an alternative embodiment, X₁ and X₃ represent C, X₄ and X₅ representCH and X₂ represents nitrogen (i.e. a ring system of formula (e)).

In an alternative embodiment, X₁ and X₃ represent C, X₄ represents CHand X₂ and X₅ represent nitrogen (i.e. a ring system of formula (f)).

In an alternative embodiment, X₁ and X₂ represent C, X₃ representsnitrogen, X₄ represents CR³ (e.g. CH) and X₅ represents CR³ (e.g. C-Me)(i.e. an example of a ring system of formula (h)).

In an alternative embodiment, X₁ and X₂ represent C, X₄ and X₅ representCH and X₃ represents nitrogen (i.e. a ring system of formula (j)).

In an alternative embodiment, X₁ and X₂ represent C, X₄ represents CHand X₃ and X₅ represent nitrogen (i.e. a ring system of formula (k)).

In an alternative embodiment, X₂ and X₃ represent C, X₅ represents CHand X₁ and X₄ represent nitrogen (i.e. a ring system of formula (r)).

In one embodiment, X₁, X₃ and X₅ represent C and X₂ and X₄ representnitrogen (i.e. an example of a ring system of formula (a)).

In an alternative embodiment, X₁, X₃, X₄ and X₅ represent C and X₂represents nitrogen (i.e. an example a ring system of formula (e)).

In an alternative embodiment, X₁, X₃ and X₄ represent C and X₂ and X₅represent nitrogen (i.e. an example a ring system of formula (f)).

In an alternative embodiment, X₁ and X₂ represent C, X₃ representsnitrogen, X₄ represents CR³ (e.g. CH) and X₅ represents CR⁶ (e.g. C-Me)(i.e. an example a ring system of formula (h)).

In an alternative embodiment, X₁, X₂, X₄ and X₅ represent C and X₃represents nitrogen (i.e. an example a ring system of formula (j)).

In an alternative embodiment, X₁, X₂ and X₄ represent C and X₃ and X₅represent nitrogen (i.e. an example a ring system of formula (k)).

In an alternative embodiment, X₂, X₃ and X₅ represent C and X₁ and X₄represent nitrogen (i.e. an example a ring system of formula (r)).

In one embodiment, X₂ represents C.

In one embodiment, X₃ represents N.

In one embodiment, X₄ represents CH or CR³.

In one embodiment, X₅ represents CH or CR⁶.

In one embodiment, X₁-X₅ represent a ring system of formulae (a), (e),(f), (j), (k) or (r). In a further embodiment, X₁-X₅ represent a ringsystem of formulae (a), (e) or (j). In a further embodiment, X₁-X₅represent a ring system of formula (a) or (j) In a further embodiment,X₁-X₅ represent a ring system of formula (j).

In one embodiment, when X₁, X₂ and X₅ represents C, X₃ representsnitrogen and A represents phenyl, B is a group other than a heterocyclicgroup.

In one embodiment, when X₁, X₂, X₄ and X₅ represents C, X₃ representsnitrogen and A represents pyrimidinyl, B represents a group other than aheterocyclic group.

In one embodiment, when X₁, X₃, X₄ and X₅ represents C, X₂ representsnitrogen and A represents pyrimidinyl, B represents a group other than aheterocyclic group.

In one embodiment, when X₁, X₃ and X₅ represent C and X₂ and X₄represent nitrogen, R^(a) is a group other than ═O.

In one embodiment of compounds of formula (Ia), when X₂, X₃, X₄ and X₅represent C, X₁ represents nitrogen, A represents thiazolyl, R^(a)represents a group other than —COR^(x)R^(y).

In one embodiment, when X₂ and X₃ represents C and X₁ representsnitrogen, A represents a group other than pyrazinyl.

In one embodiment, when X₂, X₃, X₄ and X₅ represent C and X₁ representsnitrogen, B represents a group other than phenyl.

In one embodiment, when X₄ represents nitrogen, X₁ represents a groupother than nitrogen.

Examples of ring systems encompassed by the definition A are shown inthe following formulae A1-A15, wherein B can be optionally substitutedby one or more R¹ as shown in formula (I):

The group A12 can be any tautomer of imidazole e.g. A12a.

In one embodiment, A is a group other than pyrazolyl. In one embodiment,A is a group other than imidazolyl.

In one embodiment, A represents a group selected from any one offormulae A1 to A10 and A12-A15. In a further embodiment, A is selectedfrom A2, A14 and A15. In a further embodiment, A is selected from A2.

In one embodiment, A represents a 5- or 6-membered aromatic group.

In one embodiment, A represents a 5-membered aromatic group.

In one embodiment, A represents a non-aromatic group.

In one embodiment, A represents a 6-membered aromatic group.

In one embodiment, A represents pyridin-3-yl or phenyl.

In one embodiment, A represents a monocyclic aromatic carbocyclic orheterocyclic ring system having for example a 5, 6 or 7 membered ring.In a further embodiment, A represents a 6 membered carbocyclic ring. Ina yet further embodiment, A represents a phenyl group (i.e. a ringsystem of formula A1) optionally substituted by one or more (e.g. 1, 2or 3) R^(a) groups. In one embodiment, A represents unsubstituted phenylor phenyl substituted with an —(CH₂)_(s)—CONR^(x)R^(y) (e.g. —CONH₂),—(CH₂)_(s)—CN (e.g. —CN), C₁₋₆ alkyl (e.g. methyl) or C₁₋₆ alkoxy (e.g.methoxy) group.

In one embodiment, A represents a monocyclic aromatic carbocyclic orheterocyclic ring system having for example a 5, 6 or 7 membered ring.In a further embodiment, A represents a 6 membered carbocyclic ring. Ina yet further embodiment, A represents a phenyl group (i.e. a ringsystem of formula A1) or a pyridyl group (i.e. a ring system of formulaA2 or A3) optionally substituted by one or more (e.g. 1, 2 or 3) R^(a)groups. In one embodiment, A represents unsubstituted phenyl or phenylsubstituted with an —(CH₂)_(s)—CONR^(x)R^(y) (e.g. —CONH₂),—(CH₂)_(s)—CN (e.g. —CN), halogen (e.g. fluorine), C₁₋₆ alkyl (e.g.methyl), C₁₋₆ alkanol (e.g. —CH₂OH) or —OR^(x) (e.g. methoxy or—OCH(Me)₂) group.

In one embodiment, A represents a group other than pyridinyl orpyrazinyl when B represents phenyl, pyridyl or pyrazinyl.

In one embodiment, A represents a group other than pyrazinyl. In oneembodiment, A represents a group other than pyrimidinyl. In oneembodiment, A represents a group other than pyridinyl or pyrimidinyl. Ina further embodiment, A represents unsubstituted phenyl.

In one embodiment, A represents a 6 membered monocyclic aromaticcarbocyclic or heterocyclic ring system (e.g. phenyl or pyridyl),substituted by NH—B—(R¹)_(q) at the 3-position or 5-position. When Arepresents phenyl, in one embodiment NH—B—(R¹)_(q) is present at the3-position of the phenyl with respect to the position of attachment toX₁.

In one embodiment, A represents a 6 membered monocyclic aromaticcarbocyclic or heterocyclic ring system (e.g. phenyl or pyridyl),substituted by NH—B—(R¹)_(q) at the 5-position and further optionallysubstituted by a single R^(a) group at the 3-position.

When V and W represent a bond, examples of aromatic ring systemsencompassed by the definition B—NH— are shown in the following formulaeB1-B47, in particular B1-B45:

When V and W represent a bond, particular examples of B rings includeB1, B4 and B9. Further particular examples of B rings include B19-21,B22, B24, B25, B27-36, B38-40, B42 and B44.

When V represents CH₂, one example of an aromatic ring systemencompassed by the definition B—NH— is shown in the following formulaB48:

When V and W represent a bond, examples of saturated or partiallysaturated ring systems encompassed by the definition B—NH— are shown inthe following Table 1:

TABLE 1

In one embodiment, B represents —V-aryl. In one embodiment, V representsa group other than —C(H)(Me)-. In one embodiment, V represents a bond orCH₂. In a further embodiment, V represents a bond. In one embodiment,the aryl group of B represents a phenyl group.

In one embodiment, B represents —W-heterocyclyl.

In one embodiment, W represents a group other than —C(H)(Me)-. In afurther embodiment, W represents a bond.

In one embodiment, when B represents a —W-heterocyclyl group, Wrepresents a bond.

In one embodiment, the aryl or heterocyclyl group of B represents amonocyclic aromatic carbocyclic or heterocyclic ring system having forexample a 5, 6 or 7 membered ring (e.g. phenyl, pyridyl, pyrazinyl,triazolyl or thiadiazolyl). In a further embodiment, the heterocyclylgroup of B represents a 5 or 6 membered heterocyclic ring (e.g. pyridyl,pyrazinyl, triazolyl or thiadiazolyl). In a further embodiment, theheterocyclyl group of B represents a 5 or 6 membered heterocyclic ring(e.g. pyridyl, pyrazinyl, triazolyl, oxadiazolyl, imidazolyl orthiadiazolyl). In a yet further embodiment, the heterocyclyl group of Brepresents a 5 membered heterocyclic ring group selected from compoundsof formula B^(a), B^(b) and B^(c):

wherein Xa is selected from NH, CH, and S; Xb is selected from C, N, O,and S; Xc is selected from N, and O; Xd is selected from C, N, O, and S;Xe is selected from C and N and

represents the point of attachment to NH;

wherein the dotted line

can represent a single, or double bond;

-   Xa is selected from NH, CH, and S; Xb is selected from C, N, O, and    S; Xc is selected from C, S and N; Xd is selected from C, N, O, and    S; Xe is selected from C and N; and    represents the point of attachment to NH;

B^(c)wherein the dotted line

can represent a single, or double bond;

-   Xa is selected from NH, CH, and S; Xb is selected from C, N, O, and    S; Xc is selected from C, N, O, and S; Xd is selected from C, N, O,    and S; Xe is selected from C and N; and    represents the point of attachment to NH.

In a yet still further embodiment, the heterocyclyl group of Brepresents oxadiazolyl, imidazolyl, triazolyl or thiadiazolyl. In afurther embodiment, the heterocyclyl group of B represents triazolyl orthiadiazolyl. In a still yet further embodiment, the heterocyclyl groupof B represents thiadiazolyl.

In one embodiment, q represents 0 or 1. When q represents 1, in oneembodiment, R¹ represents C₁₋₆ alkyl (e.g. methyl). When q represents 1,in an alternative embodiment, R¹ represents or —(CH₂)_(s)—NR^(x)R^(y)(e.g. —NH₂). In a further embodiment, q represents 0.

In one embodiment, X₅ represents CH or nitrogen.

In one embodiment, X₅ represents CH, nitrogen or C═O.

In one embodiment, R² represents a —CONR⁷R⁸ or —COOR^(z) group (e.g.—COOH). In a further embodiment, R² represents a —CONR⁷R⁸ group.

In one embodiment, R² represents a —COR^(x) group.

In one embodiment, R^(x) represents C₁₋₆ alkyl (e.g. methyl, ethyl orisopropyl) or C₃₋₈ cycloalkyl (e.g. cyclopropyl, cyclobutyl orcyclopentyl).

When R² represents a —COR^(x) group, in one embodiment R^(x) representsC₁₋₆ alkyl (e.g. methyl, ethyl or isopropyl) or C₃₋₈ cycloalkyl (e.g.cyclopropyl, cyclobutyl or cyclopentyl).

In one embodiment, R⁶ represents hydrogen.

In one embodiment, R⁶ represents C₁₋₆ alkoxy (e.g. unsubstituted C₁₋₆alkoxy).

In one embodiment, R⁷ and R⁸ both represent hydrogen or C₁₋₆ alkyl (e.g.methyl).

In a further embodiment, one of R⁷ and R⁸ represents hydrogen and theother represents C₁₋₆ alkyl (e.g. methyl, ethyl or isopropyl) optionallysubstituted by an —OR^(x) group (e.g. —(CH₂)₂—O-Me), C₃₋₈ cycloalkyl(e.g. cyclobutyl) or heterocyclyl (e.g. thiophenyl). In a furtherembodiment, one of R⁷ and R⁸ represents hydrogen and the otherrepresents C₁₋₆ alkyl (e.g. methyl).

In a further embodiment, R⁷ and R⁸ together with the nitrogen atom towhich they are attached form a nitrogen containing heterocyclyl ringoptionally substituted by one or more (e.g. 1, 2 or 3) R^(b) groups.

In a further embodiment, R⁷ and R⁸ together with the nitrogen atom towhich they are attached form a nitrogen containing heterocyclyl ringoptionally substituted by one or more (e.g. 1, 2 or 3) R^(a) groups.

In a further embodiment, R⁷ and R⁸ together with the nitrogen atom towhich they are attached form a nitrogen containing heterocyclyl ring(e.g. azetidinyl or pyrrolidinyl) optionally substituted by one or more(e.g. 1, 2 or 3) R^(b) groups (e.g. —OR^(x) (e.g. —OH), halogen (e.g.fluorine) or —Y-aryl (e.g. -phenyl)). In a further embodiment, R⁷ and R⁸together with the nitrogen atom to which they are attached form anitrogen containing heterocyclyl ring (e.g. azetidinyl).

In one embodiment, Y represents —O—(CH₂)_(s)— (e.g. —O—CH₂—).

In one embodiment, Y and Z independently represent a bond,—CO—(CH₂)_(s)—, —COO—, —(CH₂)_(n)—, —NR^(x)—(CH₂)_(n)—,—(CH₂)_(n)—NR^(x)—, —CONR^(x)—, —NR^(x)CO—, —SO₂NR^(x)—, —NR^(x)SO₂—,—NR^(x)CONR^(y)—, —NR^(x)CSNR^(y)—, —O—(CH₂)_(s), —(CH₂)_(s)—O—, S—,—SO— or —(CH₂)_(s)—SO₂—.

In one embodiment, Y and Z independently represent —CO—, —O—(CH₂)_(s)—or —NH—(CH₂)_(s)— (e.g. NH).

In one embodiment, Y and Z independently represent —CO—, —O—(CH₂)_(s) or—NH—(CH₂)_(n)—

In one embodiment, Z represents a bond, CO, —(CH₂)_(n)— (e.g. —CH₂—,—(CH₂)₂ or —(CH₂)₃) or —O—. In a further embodiment, Z represents —O—COor —(CH₂)_(n)— (e.g. —CH₂—). In a yet further embodiment, Z represents—(CH₂)_(n)— (e.g. —CH₂—).

In one embodiment, Y and Z independently represent a bond.

In one embodiment, R^(b) independently represents an R^(a) group or a—Y-aryl or —Z-heterocyclyl group wherein said aryl and heterocyclylgroups may be optionally substituted by one or more (e.g. 1, 2 or 3)R^(a) groups.

In one embodiment, R^(e), R^(f) and R^(w) independently representhydrogen or methyl. In a further embodiment, R^(e), R^(f) and R^(w)represent hydrogen.

In one embodiment, n represents 1.

In one embodiment, the compound of formula (I) is a compound of formula(Ic) or (Id):

wherein

-   A represents an aromatic carbocyclic or heterocyclic group which may    be optionally substituted by one or more (e.g. 1, 2 or 3) R^(a)    groups;-   B represents an aromatic or non-aromatic carbocyclic or heterocyclic    group;-   R⁴ and R⁵ independently represent hydrogen, C₁₋₆ alkyl, C₂₋₆    alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, C₁₋₆    alkanol, haloC₁₋₆ alkyl, —(CH₂)_(n)—NR^(x)R^(y),    —(CH₂)_(s)—COOR^(z), —(CH₂)_(n)—O—(CH₂)_(m)—OH, —(CH₂)_(n)-aryl,    —(CH₂)_(n)—O-aryl, —(CH₂)_(n)-heterocyclyl or    —(CH₂)_(n)—O-heterocyclyl wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,    C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, aryl and    heterocyclyl groups may be optionally substituted by one or more    (e.g. 1, 2 or 3) R^(a) groups;-   R^(x), R^(y) and R^(z) independently represent hydrogen, C₁₋₆ alkyl,    C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkanol, hydroxy, C₁₋₆ alkoxy,    haloC₁₋₆ alkyl, —CO—(CH₂)_(n)—C₁₋₆ alkoxy, C₃₋₈ cycloalkyl or C₃₋₈    cycloalkenyl;-   R² represents a —CONR⁷R⁸, —COR^(x) or —COOR^(z) group;-   R⁷ and R⁸ independently represent hydrogen, C₁₋₆ alkyl, C₂₋₆    alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, aryl,    heterocyclyl or R⁷ and R⁸ together with the nitrogen atom to which    they are attached may form a nitrogen containing heterocyclyl ring,    wherein said C₁₋₆ alkyl, aryl and heterocyclyl may be optionally    substituted by one or more (e.g. 1, 2 or 3) R^(a) groups;-   R^(a) represents halogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,    C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, —OR^(x), —O—(CH₂)_(n)—OR^(x),    haloC₁₋₆ alkyl, haloC₁₋₆ alkoxy, C₁₋₆ alkanol, ═O, ═S, nitro,    —(CH₂)_(s)—CN, —S—R^(x), —SO—R^(x), —SO₂—R^(x), —COR^(x),    —(CR^(x)R^(y))_(s)—COOR^(z), —(CH₂)_(s)—CONR^(x)R^(y),    —(CH₂)_(s)—NR^(x)R^(y), —(CH₂)_(s)—NR^(x)COR^(y),    —(CH₂)_(s)—NR^(x)SO₂—R^(y), —OCONR^(x)R^(y),    —(CH₂)_(s)—NR^(x)CO₂R^(y), —O—(CH₂)_(s)—CR^(x)R^(y)—(CH₂)_(t)—OR^(z)    or —(CH₂)_(s)—SO₂NR^(x)R^(y) groups;-   R¹ and R^(b) represents an R^(a) group or a —Y-aryl or    —Z-heterocyclyl group wherein said aryl and heterocyclyl groups may    be optionally substituted by one or more (e.g. 1, 2 or 3) R^(a)    groups;-   Y and Z independently represent a bond, —CO—(CH₂)_(s)—, —COO—,    —(CH₂)_(n)—, —NR^(x)—(CH₂)_(n)—, —(CH₂)_(n)—NR^(x)—, —CONR^(x)—,    —NR^(x)CO—, —SO₂NR^(x)—, —NR^(x)SO₂—, —NR^(x)CONR^(y)—,    —NR^(x)CSNR^(y)—, —O—(CH₂)_(s)—, —(CH₂)_(s)—O—, S—, —SO— or    —(CH₂)_(s)—SO₂—;-   m and n independently represent an integer from 1-4;-   s and t independently represent an integer from 0-4;-   q represents an integer from 0-2;-   aryl represents a carbocyclic ring;-   heterocyclyl represents a heterocyclic ring;-   or a pharmaceutically acceptable salt, solvate or derivative    thereof.

In one embodiment of compounds of formula (Ic) and (Id), Y and Zindependently represent a bond, —CO—(CH₂)_(s)—, —COO—, —(CH₂)_(n)—,—NR^(x)—(CH₂)_(s)—, —(CH₂)_(s)—NR^(x)—, —CONR^(x)—, —NR^(x)CO—,—SO₂NR^(x)—, —NR^(x)SO₂—, —NR^(x)CONR^(y)—, —NR^(x)CSNR^(y)—,—O—(CH₂)_(s)—, S—, —SO— or —(CH₂)_(s)—SO₂—.

In one embodiment, the compound of formula (I) is a compound selectedfrom Examples 1-4. In a further embodiment, the compound of formula (I)is a compound of Example 2.

In the specification, references to formula (I) include formulas such as(Ia), and (Ib), and sub-groups, examples or embodiments of formulae (I),(Ia), (Ib), (Ic) and (Id) unless the context indicates otherwise.

Thus for example, references to inter alia therapeutic uses,pharmaceutical formulations and processes for making compounds, wherethey refer to formula (I), are also to be taken as referring to formulae(I), (Ia), (Ib), (Ic) and (Id), and sub-groups, examples or embodimentsof formulae (I), (Ia), (Ib), (Ic) and (Id).

Similarly, where preferences, embodiments and examples are given forcompounds of the formula (I), they are also applicable to formulae (I),(Ia), (Ib), (Ic) and (Id), and sub-groups, examples or embodiments offormulae (I), (Ia), (Ib), (Ic) and (Id), unless the context requiresotherwise.

Methods for the Preparation of Compounds of Formula (I)

In this section, as in all other sections of this application unless thecontext indicates otherwise, references to formula (I) also include allother sub-groups and examples thereof as defined herein.

Compounds of the formula (I) can be prepared in accordance withsynthetic methods well known to the skilled person. In particularcompounds of formula (I) are readily prepared by palladium mediatedcoupling chemistries between aromatic chloro, bromo, iodo, orpseudo-halogens such as a trifluoromethanesulphonate (triflate) ortosylate compounds, and aromatic boronic acids or stannane derivatives.In particular, Suzuki coupling chemistry is broadly applicable tosynthesis of these compounds. The Suzuki reaction can be carried outunder typical conditions in the presence of a palladium catalyst such asbis(tri-t-butylphosphine)palladium,tetrakis-(triphenylphosphine)palladium or a palladacycle catalyst (e.g.the palladacycle catalyst described in Bedford, R. B. and Cazin, C. S.J. (2001) Chem. Commun., 1540-1541) and a base (e.g. a carbonate such aspotassium carbonate) as discussed in more detail below. The reaction maybe carried out in polar solvent, for example an aqueous solvent system,including aqueous ethanol, or an ether such as dimethoxyethane ordioxane, and the reaction mixture is typically subjected to heating, forexample to a temperature of 80° C. or more, e.g. a temperature in excessof 100° C.

In the process sections references to R and R′ are used to indicategroups as defined in R⁷ and R⁸, or protected forms thereof.

As illustrated in Scheme 1A, the imidazo[1,2-a]pyridine core can besynthesised from commercially available starting materials as outlinedbelow to give a 3,7-disubstituted ring.

2-amino-isonicotinic acid methyl ester in an appropriate solvent andbase can be cyclised under reflux with chloroacetaldehyde to give theimidazopyridine ring.

For synthesis of the R₂ group of compounds of formula (I) the carboxylicester is hydrolysed, for example using standard ester hydrolysisconditions such as aqueous base and heating. The carboxylic acid or anactivated derivative thereof can then be reacted with the appropriateamine to form the amide (Scheme 1A).

The coupling reaction between the carboxylic acid and the amine ispreferably carried out in the presence of a reagent of the type commonlyused in the formation of peptide linkages. Examples of such reagentsinclude 1,3-dicyclohexylcarbodiimide (DCC) (Sheehan et al, J. Amer.Chem. Soc., 1955, 77, 1067),1-ethyl-3-(3′-dimethylaminopropyl)-carbodiimide (referred to hereineither as EDC or EDAC but also known in the art as EDCI and WSCDI)(Sheehan et al, J. Org. Chem., 1961, 26, 2525), uronium-based couplingagents such as O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) orO-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU) and phosphonium-based coupling agents such as1-benzo-triazolyloxytris-(pyrrolidino)phosphonium hexafluorophosphate(PyBOP) (Castro et al, Tetrahedron Letters, 1990, 31, 205).Carbodiimide-based coupling agents are advantageously used incombination with 1-hydroxy-7-azabenzotriazole (HOAt) (L. A. Carpino, J.Amer. Chem. Soc., 1993, 115, 4397) or 1-hydroxybenzotriazole (HOBt)(Konig et al, Chem. Ber., 103, 708, 2024-2034). Preferred couplingreagents include TBTU, EDC (EDAC) or DCC in combination with HOAt orHOBt.

The coupling reaction is typically carried out in a non-aqueous,non-protic solvent such as acetonitrile, 1,4-dioxane,dimethylsulphoxide, dichloromethane, dimethylformamide orN-methylpyrrolidine, or in an aqueous solvent optionally together withone or more miscible co-solvents. The reaction can be carried out atroom temperature or, where the reactants are less reactive (for examplein the case of electron-poor anilines bearing electron withdrawinggroups such as sulphonamide groups) at an appropriately elevatedtemperature. The reaction may be carried out in the presence of anon-interfering base, for example a tertiary amine such as triethylamineor N,N-diisopropylethylamine.

As an alternative, a reactive derivative of the carboxylic acid, e.g. ananhydride or acid chloride, may be used. Reaction with a reactivederivative such an anhydride, is typically accomplished by stirring theamine and anhydride at room temperature in the presence of a base suchas pyridine.

Amines for use in the reaction can be obtained from commercial sourcesor can be prepared by any of a large number of standard syntheticmethods well known by those skilled in the art, see for example AdvancedOrganic Chemistry by Jerry March, 4^(th) Edition, John Wiley & Sons,1992, and Organic Syntheses, Volumes 1-8, John Wiley, edited by JeremiahP. Freeman (ISBN: 0-471-31192-8), 1995, and see also the methodsdescribed in the experimental section below. For example the appropriatenitro-compound may be reduced to give the corresponding amino-compound.The reduction may be carried out by standard methods such as catalytichydrogenation, for example in the presence of palladium on carbon in apolar solvent such as ethanol or dimethylformamide at room temperature.As an alternative, reduction may be effected using a reducing agent suchas tin (II) chloride in ethanol, typically with heating, for example tothe reflux temperature of the solvent.

The imidazo[1,2-a]pyridine-7-derivative, for example theimidazo[1,2-a]pyridine-7-carboxylic acid methyl ester or amide, in anappropriate solvent can then be iodinated, for example usingN-iodosuccinimide at room temperature.

Appropriate functionality can then be added at the halogenated position,for example using a range of metal-catalysed reactions. In particular,appropriately functionalised boronic acids, trifluoroboronates, or theirboronate esters may react with the aryl halide. This transformation,commonly known as the Suzuki reaction, has been reviewed by Rossi et al(2004), Synthesis 15, 2419.

The Suzuki reaction is often carried out in mixtures of water andorganic solvents. Examples of suitable organic solvents include toluene,tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, acetonitrile,N-methylpyrrolidinone, ethanol, methanol and dimethylformamide. Thereaction mixture is typically subjected to heating, for example to atemperature in excess of 100° C. The reaction is carried out in thepresence of a base. Examples of suitable bases include sodium carbonate,potassium carbonate, cesium carbonate and potassium phosphate. Examplesof suitable catalysts include bis(tri-t-butylphosphine)palladium(0),tris(dibenzylideneacetone)dipalladium(0),bis(triphenylphosphine)palladium(II) chloride, palladium(II) acetate,tetrakis(triphenylphosphine)palladium(0), bis(tricyclohexylphosphine)palladium(0),[1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II),dichlorobis(tri-o-tolylphosphine)palladium(II),2′-(dimethylamino)-2-biphenylyl-palladium(II) chloridedinorbornylphosphine complex and2-(dimethylamino)ferrocene-1-yl-palladium(II) chloridedinorbornylphosphine complex. In some cases additional ligands may beadded to facilitate the coupling reaction. Examples of suitable ligandsinclude tri-t-butylphosphine, 2,2-bis(diphenylphosphino)-1,1-binaphthyl,triphenylphosphine, 1,2-bis(diphenylphosphino)ethane,1,1′-bis(diphenylphosphino)ferrocene, tricyclohexylphosphine,9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene,1,3-bis(diphenylphosphino)propane, 2-(di-t-butylphosphino)biphenyl,2-dicyclohexylphosphino-2′-(n,n-dimethylamino)-biphenyl,tri-o-tolylphosphine, 2-(dicyclohexylphosphino)biphenyl,2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl,tri(2-furyl)phosphine, 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyland 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl.

Other examples of possible metal catalysed functionalisations of thehalide are reactions with organo-tin reagents (the Stille reaction),with Grignard reagents and reaction with nitrogen nucleophiles. Ageneral overview, and further leading references, of thesetransformations is presented in ‘Palladium Reagents and Catalysts’ [JiroTsuji, Wiley, ISBN 0-470-85032-9] and Handbook of OrganoPalladiumChemistry for Organic Synthesis [Volume 1, Edited by Ei-ichi Negishi,Wiley, ISBN 0-471-31506-0].

In particular, one reaction which can be utilised is theBuchwald-Hartwig type reaction (see Review: J. F. Hartwig (1998), Angew.Chem. Int. Ed. 37, 2046-2067) which provides a means forpalladium-catalyzed synthesis of aryl amines. The starting materials arearyl halides or pseudohalides (for example triflates) and primary orsecondary amines, in the presence of a strong base such as sodiumtert-butoxide and a palladium catalyst such astris-(dibenzylideneacetone)-di-palladium (Pd₂(dba)₃), or2,2′-bis(diphenylphosphino)-1′1-binaphthyl (BINAP).

In particular, for synthesis compounds of formula (I) the aryl halidecan be reacted with 3-aminobenzeneboronic acid using an appropriatemetal catalyst e.g. bis(triphenylphosphine)palladium(II) chloride toform the amino precursor for secondary amine bond formations.

This sequence of reactions outlined in Scheme 1A can be alternated asoutlined in Scheme 1B or 1C.

In Scheme 1B, the imidazo[1,2-a]pyridine-7-carboxylic acid methyl esteris iodinated first and the metal-catalysed coupling reaction performed,before conversion of the methyl ester to the amide group R₂.

In Scheme 1C, the imidazo[1,2-a]pyridine-7-amide is synthesized directlyfrom the 4-amide-pyridin-2-ylamine and is then iodinated and used in themetal-catalysed coupling reaction. This reaction scheme is particularlysuitable for synthesizing compounds where R² is CONH₂.

Alternatively the 4-chloro-pyridin-2-ylamine or4-bromo-pyridin-2-ylamine in an appropriate solvent and base can becyclised under reflux with chloroacetaldehyde to give the7-halo-imidazopyridine ring (as shown in Scheme 2). The halogenfunctionality at the 7-position of the imidazo[1,2-a]pyridine can thenbe converted to an amide by either of the two routes outlined in Scheme2.

The halide can be converted to the nitrile using CuCN inN-methylpyrrolidine at reflux (for example as described in Funhoff, D.J. H et al, Angew. Chem. Int. Ed. 1986, 25(8), 724) or CuCN in DMF,which is then hydrolysed with an alkali metal hydroxide such aspotassium hydroxide to give the acid and/or the amide. Where a mixtureof the acid and amide are formed, they may be separated according tostandard methods such as chromatography. The acid can then be coupledwith an amine of the formula under typical amide coupling conditions ofthe type described above to give the compound of the formula (I).

Alternatively the halide can be converted to the acid usingn-butyllithium or magnesium and subsequent reaction of the intermediatewith a carbonylating agent such as CO₂ to produce the carboxylic acidfor use as a compound of formula (I) or for conversion to the amide orester. The amide can be accessed directly from the halide either throughtransmetallation with ^(n)BuLi and subsequent quenching with anappropriate isocyanate (Pansegran, P. D. et al, JACS, 1988, 110, 7178)or via carbonylation with carbon monoxide and in the presence of theappropriate amine and catalytic[P,P′-1,3-bis(di-1-propylphosphino)propane][P-1,3-bis(di-iso-propylphosphino)propane]palladium(0) in a solvent such as xylene at heating (e.g. to 150° C.) (forexample as described in Ben-David, Y. et al, JACS, 1989, 111(23), 8742).

In addition, the halide can be converted using carbon monoxide andpalladium catalyst to the aldehyde, which can then be oxidised to thecarboxylic acid using an oxidising agent, such as permanganate orchromic acid, and then undergo conversion to the amide using standardcoupling conditions described previously or esterified to the ester. Thehalide can also be converted directly to the ester using carbonmonoxide, palladium catalyst and the appropriate alcohol. This can thenbe a compound of formula (I) or hydrolysed to the acid, or thenhydrolysed to the acid and converted to the amide, or converted directlyto the amide.

The halide could also be converted directly to the dimethylamide usingtrimethylsilyl-dimethyl amide and reacting withbis(tri-^(t)butylphosphine)palladium and heating to 100° C. as describedin Cunico, R. F., Organic Letters, 2002, 4 (24), 4357.

Other conversions of aromatic bromides to aromatic aldehydes can takeplace using the Stille carbonyl synthesis (Stille, JACS, 1983, 105,7175), or the Bodroux-Chichibabin-aldehyde synthesis described inEinchorn, J, Tetrahedron Lett., 1983, 27, 1791. The aldehyde can then beoxidised to the acid and converted to an amide as described above.

Polyfunctional 2-amino-5-bromopyridines or the aromatic bromides can beconverted to aldehyde via Grignard type formation and quenching with DMF(Misra, Bioorg. Med. Chem. Lett., 2004, 14(11), 2973) or they can beconverted to ethyl esters via standard palladium carbonylation in thepresence of alcohol (Cheung, M. Heterocycles, 2001, 55, 1583).

Alternatively the 4-methyl-pyridin-2-ylamine can be used in thecyclisation reaction to give the 7-methyl-imidazo[1,2-a]pyridine ring,which alternatively is commercially available. The methyl can then beoxidised to the aldehyde using the Étard reaction or carboxylic acidusing an oxidising agent such as permanganate. The Étard reactioninvolves the direct oxidation of an aromatic or heterocyclic boundmethyl group to an aldehyde using chromyl chloride.

Alternatively the ethyl imidazo[1,2-a]pyridine-7-carboxylate, which isalso commercially available, can be used as the startpoint for the amideconversion or iodinations and metal-catalysed reactions.

Ketones, where R² is COR^(x), can be synthesized from the correspondingcarboxylic acid via the N,O-dimethylhydroxamic acid (Weinreb Amide) orthe N-methyl,O-t-butyl hydroxamic acid (Weinreb type Amide) intermediateand subsequent reaction with the appropriate Grignard reaction (Labeeuw,O. et al Tetrahedron Lett 2004, 45 (38), 7107-7110). Derivatisation tothe corresponding Weinreb Amide uses N,O-dimethylhydroxylaminehydrochloride as described in L. De Luca, G. Giacomelli, M. Taddei, J.Org. Chem., 2001, 66, 2534-2537. Conversion of the standard aromaticWeireb Amide to a methyl ketone requiresmethylene-triphenyl-lambda*5*-phosphane in a solvent such attetrahydrofuran as reported in Murphy, J. A. et al Org Lett 2005, 7 (7),1427-1429.

Alternatively ketones can be prepared from the chloride usingvinylethertin (Stille type) coupling with haloaromatic orhaloheteroaromatic. As an example the acetyl ketone can be prepared byheating tributyl-(1-ethoxy-vinyl)-stannane, lithium chloride andtetrakis(triphenylphosphine)-palladium(0) in solvent such asacetonitrile or via a Heck type reaction reported in Mo, J. Angew Chem,Int Ed, 2006, 45(25), 4152.

A range of compounds of formula (I) can be accessed by use of3-aminobenezeboronic acid in the Suzuki reaction and subsequentderivatisation. In particular, as outlined Scheme 3, the aminefunctionality introduced can be used to synthesise secondary aminecompounds.

Primary amines can be prepared by reduction of the correspondingnitro-compound under standard conditions. The reduction may be effected,for example by catalytic hydrogenation in the presence of a catalystsuch as palladium on carbon in a polar solvent such as ethanol ordimethylformamide at room temperature.

Compounds of the formula (I) containing a secondary amine group, can beprepared from the amino compounds by a number of methods. Reductiveamination with an appropriately substituted aldehyde or ketone can becarried out in the presence of a variety of reducing agents (seeAdvanced Organic Chemistry by Jerry March, 4^(th) Edition, John Wiley &Sons, 1992, p 898-900). For example, reductive amination can be carriedout in the presence of sodium triacetoxyborohydride in the presence ofan aprotic solvent, such as dichloromethane, at or near ambienttemperatures. They can also be prepared by the reaction of the aminocompound in a nucleophilic displacement reaction, where the reagentcontains a leaving group such as a halogen.

In addition the thiadiazolylamino compound can be synthesised by use ofthe appropriate substituted boronic acid e.g.3-([1,3,4]Thiadiazol-2-ylamino)-phenyl boronic acid pinacol ester or3-(5-Methyl-[1,3,4]thiadiazol-2-ylamino)-phenyl boronic acid pinacolester in the Suzuki reaction with an appropriately substitutedimidazo[1,2-a]pyrimidine. These can be synthesised as described herein.

Alternatively the secondary amine can be formed by cyclisation of anappropriate group to form a ring. Amino-thiadiazole compounds can besynthesised as described in Scheme 4.

This involves reacting the amino compound in anhydrous solvent e.g.toluene, with 1,1′-thiocarbonyldi-2(1H)-pyridone. Typical reactionconditions are heating for 1 hour, work up and then treatment withhydrazine hydrate to form the thiosemicarbazide. This is then cyclisedunder conditions, such as through addition of diethyl chlorophosphatedropwise. This may also generate an alternate cyclisation product andhence separation may be required.

Alternate amino-heterocyclic groups can be formed by known heterocyclicring formation reactions. For example the amino-triazole (e.g.3H-[1,2,3]triazol-4-yl)-amine) can be formed by reaction of sodiumnitrite in H₂O with the amine in acid e.g. 2N HCl, followed by additionof aminoacetonitrile hydrogen sulphate in H₂O. After an appropriateperiod of time NaOAc is added and rearrangement to the desiredheterocycle is achieved by heating in solvent e.g. ethanol, for 16hours.

Appropriate starting material and reagents for these reactions can beobtained commercially or by any of a large number of standard syntheticmethods well known to those skilled in the art, for example see AdvancedOrganic Chemistry by Jerry March, 4^(th) Edition, John Wiley & Sons,1992, and Organic Syntheses, Volumes 1-8, John Wiley, edited by JeremiahP. Freeman (ISBN: 0-471-31192-8), 1995, and see also the methodsdescribed in the experimental section below. For example a range ofappropriate functionalized aniline and amino pyridine startingmaterials, and metal catalysts are commercially available.

Many boronates, for example boronic acids, esters or trifluoroborates,suitable for use in preparing compounds of the invention arecommercially available, for example from Boron Molecular Limited ofNoble Park, Australia, or from Combi-Blocks Inc. of San Diego, USA.Where the appropriately substituted boronate is not commerciallyavailable, they can be prepared by methods known in the art, for exampleas described in the review article by Miyaura, N. and Suzuki, A. (1995)Chem. Rev. 95, 2457. Thus, boronates can be prepared by reacting thecorresponding bromo-compound with an alkyl lithium such as butyl lithiumand then reacting with a borate ester e.g. (^(i)PrO)₃B. The reaction istypically carried out in a dry polar solvent such as tetrahydrofuran ata reduced temperature (for example −78° C.). Boronate esters (forexample a pinacolatoboronate) can also be prepared from a bromo-compoundby reaction with a diboronate ester such as bis(pinacolato)diboron inthe presence of a phosphine such as tricyclohexyl-phosphine and apalladium (0) reagent such as tris(dibenzylideneacetone)-dipalladium(0). The formation of the boronate ester is typically carried out in adry polar aprotic solvent such as dioxane or DMSO with heating to atemperature of up to 100° C., for example around 80° C. The resultingboronate ester derivative can, if desired, be hydrolysed to give thecorresponding boronic acid or converted into the trifluoroborate.

All of the reactions described above can be used to functionalisealternative heterocyclic templates of formula (I), whose synthesis isoutlined below.

Once synthesised, a range of functional group conversions can beemployed on the substituted imidazopyridine compounds to produce furthercompounds of formula (I). For example, some of the following reactionscan be used hydrogenation, hydrolysis, deprotection, and oxidation, toconvert one compound of formula (I) into an alternative compound offormula (I).

Pyrazolo[1,5-a]pyrimidines

The pyrazolo[1,5-a]pyrimidine template can be synthesised from theappropriately substituted aminopyrazole (VI) and fragments (VII) asshown in Scheme 5A, where R_(a) can be hydrogen or A-NH—B—(R¹)_(q). Thismay occur by a one step or two step process, where X_(a) and X_(b) areelectrophilic carbons (i.e. carbonyl, masked carbonyl i.e. acetal,enamine, conjugated alkenes or alkynes) (Perkin I, J. C. S. (1979),3085-3094). X_(c) is an appropriate substituent, either a group R₂ orgroups such as halogen or pseudo halogens or methyl, which will allowreaction to introduce R₂ as described herein. Cyclisation of thepyrazole (VI) with an appropriately substituted free or masked1,3-dicarbonyl derivative can be used to prepare substitutedpyrazolo[1,5-a]pyrimidines. Cyclisation occurs typically in an alcoholsolvent or in toluene or in acetic acid, and may have additives such aspiperidine, sodium ethoxide, HCl, AcOH, pTsOH, or ZnCl₂ present (J. Med.Chem. (2001), 44 (3), 350-361; Bull. Korean Chem. Soc. (2002), 23 (4),610-612; Australian Journal of Chemistry (1985), 38(1), 221-30).

A particular synthetic scheme for the preparation of disubstitutedpyrazolo[1,5-a]pyrimidines is outlined in Scheme 5B. Thepyrazolopyrimidine ring is formed by reaction of a substitutedmalonaldehyde as fragment VII with aminopyrazole. The substitutedmalonaldehyde can be substituted with methyl, or with a latentfunctionality e.g. a halogen as in 2-bromo-malonaldehyde, which allowsfurther derivatisation at this position as in the scheme shown belowusing the reactions outlined herein.

In the cyclisation reaction, the malonaldehyde in solvent is added to3-aminopyrazole followed by acid e.g. glacial acetic acid. The reagentsare then cyclised upon heating under reflux. The compound of formula (I)can then be synthesised using the oxidative and coupling processoutlined herein.

Compounds of formula (VI) and (VII) are known compounds or can beprepared by analogy to known methods. Many pyrazoles of formula (VI) arecommercially available. Alternatively they can be obtained from knownmethods e.g. from ketones in a process described in EP308020 (Merck), orthe methods discussed by Schmidt in Helv. Chim. Acta. (1956), 39,986-991 and Helv. Chim. Acta. (1958), 41, 1052-1060 or by conversion ofthe pyrazoles of formula (VI) or the compound of formula (I) where R^(a)is hydrogen, halogen, nitro, ester, or amide to the desired R¹functionality by standard methods known to a person skilled in the art.For example, where R¹ is halogen, coupling reactions with tin orpalladium chemistry could be performed as described herein.

Alternatively the pyrazolo[1,5-a]pyrimidine-6-carboxylic acid oraldehyde are commercially available and can be used in the reactionsdescribed herein to synthesise di-substitutedpyrazolo[1,5-a]pyrimidines.

Pyrazolo[1,5-a]pyrazines

Reaction of a mixture of 2-bromo-5-iodo-pyrazine and copper (I) iodideunder inert conditions in an appropriate solvent and base e.g. DMF/Et₃Nwith ethynyl-trimethylsilane using a palladium catalyst e.g. Pd(PPh₃)₄at room temperature gives 2-Bromo-5-trimethylsilanylethynyl-pyrazine.This material can be used without further purification and reacted toform 6-bromo-2-trimethylsilanyl-pyrazolo[1,5-a]pyrazine usingO-(mesitylenesulfonyl)hydroxylamine to form the N-amino adduct. This canthen be cyclised by reacting with base e.g. K₂CO₃ to formpyrazolopyrazine core (Scheme 6).

Appropriate groups can then be introduced by halogenation and reactionof the latent functionality in the metal catalysed reactions and theamide conversions at the other position as described herein.

Pyrazolo[1,5-a]pyridines

O-(Mesitylenesulfonyl)hydroxylamine is reacted with3-substituted-pyridine under inert conditions to form theN-aminopyridine which can be used without further purification (Scheme7). Cyclisation of the N-adduct using base (K₂CO₃) and2-benzenesulfonyl-3-dimethylamino-acrylic acid methyl ester in an inertatmosphere gives the 3-carboxylic acid ester pyrazolo[1,5-a]pyridine.The carboxylic ester can be removed for example by saponification usingsodium hydroxide to form the acid and then decarboxylation inpolyphosphoric acid. The bromide can then be converted to the desired R²group using the methods described herein.

Iodination with N-iodosuccinimide and metal catalysed reaction of arylhalides, can be used to introduced the required functionality asoutlined herein.

Imidazo[4,5-b]pyridines

An imidazo[4,5-b]pyridine ring system may be constructed by reaction ofan aniline with 2-chloro-3-amino pyridine as described in J.Heterocyclic Chemistry (1983), 20(5), 1339 (Scheme 8).

It will be appreciated that the resultant bicyclic ring in Scheme 8 canbe functionalised by halogenation or alkylation and converted to R² asdescribed herein.

A more functionalized intermediate could be prepared for example asoutlined in Scheme 9A based on methods described in U.S. Pat. No.6,723,735.

As described herein the aryl halides similar to that shown above mayundergo a range of metal catalysed reactions to generate the requiredcompounds of formula (I).

Alternatively they could be synthesised as outlined above in Scheme 9B.

Imidazo[4,5-c]pyridines

A 3-aryl-3H-imidazo[4,5-c]pyridine ring system may be constructed byreaction of 3H-imidazo[4,5-c]pyridine with an aryl iodide as discussedin Biorg. Med. Chem. Lett. (2004), 14, 5263 (Scheme 10).

It is reported that the regioisomeric products may be separated bychromatography. A possible way to further elaborate this material togive the desired substitution pattern is illustrated below (Scheme 11).

Reaction with an oxidizing agent, such as 3-chloro perbenzoic acid,could be used to prepare the N-oxide which may be rearranged to thedisubstituted 3H-imidazo[4,5-c]pyridine with several reagents e.g.POCl₃, SOCl₂. The regioisomeric products could then be separated bychromatography. Displacement of the halogen with potassium cyanide inDMSO or reaction with palladium and Zn(CN)₂ (Bioorg. Med. Chem. Lett.,2003, 13 (9), 1591), produces the nitrile which can be converted to theacid as outlined previously.

An alternative strategy is shown in Scheme 12. The synthesis of6-chloro-3H-imidazo[4,5-c]pyridine is described in J. Heterocyclic Chem(1965), 2(2), 196-201. The chloro group may be converted as outlineherein. Subsequent elaboration to the N-aryl compounds could then beachieved according to the conditions shown in Scheme 10.

1,5-Diaryl-1H-benzoimidazole

A synthesis of 1,5-diaryl-1H-benzoimidazoles is reported in Bioorg. Med.Chem. Lett. (2003), 13, 2485-2488 (Scheme 13).

Displacement of fluorine from 4-bromo-1-fluoro-2-nitro-benzene with anappropriate aniline followed by reduction and cyclisation with triethylorthoformate gives the bromo-benzoimidazole with the desiredsubstitution pattern. The product may be further elaborated by reactionof the bromide as described herein to give 1,5-disubstitutedbenzoimidazoles.

1,5-disubstituted benzoimidazoles may be synthesised using analogouschemistry to that described in Scheme 11.

Imidazo[1,2-c]pyrimidines

Di-substituted imidazo[1,2-c]pyrimidines can be prepared as outlined inScheme 14.

This starts from 7-chloro-imidazo[1,2-c]pyrimidine, whose synthesis hasbeen described in Yanai et al, Heterocyclic compounds. XVIII. Synthesisof imidazo[1,2-c]-pyrimidine derivatives, Yakugaku Zasshi (1974),94(12), 1503-14. This material can then be further elaborated using anyof the reactions described above.

Where the 3-position is an aryl or heteroaryl group the S_(N)Ar groupcan be replaced with a standard palladium cross coupling reaction usingsimilar chemistries as described herein (Scheme 16).

Alternatively the 6-chloropyrimid-4-ylamine can be reacted to form thebicyclic ring system and then convert the chloro to the R₂ group.

Alternatively the 6-amino-pyrimidine-4-carboxylic acid can be used asthe starting material.

Imidazo[1,2-c]pyrimidin-5-one

3,7-disubstituted imidazo[1,2-c]pyrimidin-5-ones can be prepared fromthe 7-Chloro-6H-imidazo[1,2-c]pyrimidin-5-one (CAS number 56817-09-5)whose synthesis is described in Maggiali et al (1982), Acta Naturalia del'Ateneo Parmense, 18(3), 93-101 and Bartholomew et al (1975) Journal ofOrganic Chemistry, 40(25), 3708-13.

7-Chloro-6H-imidazo[1,2-c]pyrimidin-5-one can be derivatised usingnucleophilic substitution reactions such as S_(N)Ar to add functionalityat the 7 position (Scheme 17). The S_(N)Ar reaction can be performedusing potassium cyanide, and then converted to the amide. This compoundcan then be iodinated as described above before furtherfunctionalisation using the Suzuki reaction.

Alternatively 7-Chloro-6H-imidazo[1,2-c]pyrimidin-5-one could bedirectly iodinated to the intermediate below for use in the reactionsdescribed herein (Scheme 18).

In addition, other oxo-heterocycles could be synthesized from theappropriate chloro derivative by hydrolysis. The protected compoundwould be subjected to base hydrolysis to afford the pyridone. This couldbe performed with NaOH (or NaOH/H₂O₂) in H₂O/MeOH or H₂O/dioxanefollowing procedures described in the literature for the hydrolysis ofchloropyridines (e.g. Australian J. Chem. (1984), 37(12), 2469-2477).

Imidazo[1,2-b]pyridazine

The synthesis of the Imidazo[1,2-b]pyridazine core can be performed asdescribed in Scheme 19 using a pyridazin-3-ylamine derivative.

Many methyl, carboxylic acid, carboxylic ester, or halide substitutedbicyclic or monocyclic aromatic compounds are commercially available.Therefore, these and other heterocycles, may be synthesised directlyfrom the methyl, carboxylic acid, carboxylic ester, or halidesubstituted bicyclic compounds or from the methyl, carboxylic acid,carboxylic ester, or halide substituted monocyclic aromatic compoundsusing the cyclisation reactions described herein.

Other heterocycles can be synthesised using well known reactions, forexample as described in Comprehensive Heterocyclic Chemistry I (Editedby Katritzky, A. R. and Rees, C. W. (1982) Elsevier) and ComprehensiveHeterocyclic Chemistry II (Edited by Katritzky, A. R., Rees, C. W. andScriven, E. F. V. (1996) Elsevier, ISBN 0-08-042072-9).

In many of the reactions described above, it may be necessary to protectone or more groups to prevent reaction from taking place at anundesirable location on the molecule. Examples of protecting groups, andmethods of protecting and deprotecting functional groups, can be foundin Protective Groups in Organic Synthesis (Green, T. and Wuts, P.(1999); 3rd Edition; John Wiley and Sons).

A hydroxy group may be protected, for example, as an ether (—OR) or anester (—OC(═O)R), for example, as: a t-butyl ether; a benzyl, benzhydryl(diphenylmethyl), or trityl (triphenylmethyl)ether; a trimethylsilyl ort-butyldimethylsilyl ether; or an acetyl ester (—O(═O)CH₃, —OAc). Analdehyde or ketone group may be protected, for example, as an acetal(R—CH(OR)₂) or ketal (R₂C(OR)₂), respectively, in which the carbonylgroup (>C═O) is converted to a diether (>C(OR)₂), by reaction with, forexample, a primary alcohol. The aldehyde or ketone group is readilyregenerated by hydrolysis using a large excess of water in the presenceof acid. An amine group may be protected, for example, as an amide(—NRCO—R) or a urethane (—NRCO—OR), for example, as: a methyl amide(—NHCO—CH₃); a benzyloxy amide (—NHCO—OCH₂C₆H₅, —NH-Cbz); as a t-butoxyamide (—NHCO—OC(CH₃)₃, —NH-Boc); a 2-biphenyl-2-propoxy amide(—NHCO—OC(CH₃)₂C₆H₄C₆H₅, —NH-Bpoc), as a 9-fluorenylmethoxy amide(—NH-Fmoc), as a 6-nitroveratryloxy amide (—NH-Nvoc), as a2-trimethylsilylethyloxy amide (—NH-Teoc), as a 2,2,2-trichloroethyloxyamide (—NH-Troc), as an allyloxy amide (—NH-Alloc), or as a2(-phenylsulphonyl)ethyloxy amide (—NH-Psec). Other protecting groupsfor amines, such as cyclic amines and heterocyclic N—H groups, includetoluenesulphonyl (tosyl) and methanesulphonyl (mesyl) groups and benzylgroups such as a para-methoxybenzyl (PMB) group. A carboxylic acid groupmay be protected as an ester for example, as: an C₁₋₇ alkyl ester (e.g.,a methyl ester; a t-butyl ester); a C₁₋₇ haloalkyl ester (e.g., a C₁₋₇trihaloalkyl ester); a triC₁₋₇alkylsilyl-C₁₋₇alkyl ester; or a C₅₋₂₀aryl-C₁₋₇ alkyl ester (e.g., a benzyl ester; a nitrobenzyl ester); or asan amide, for example, as a methyl amide. A thiol group may beprotected, for example, as a thioether (—SR), for example, as: a benzylthioether; an acetamidomethyl ether (—S—CH₂NHC(═O)CH₃).

Key intermediates in the preparation of the compounds of formula (I) arethe compounds of formula (II) and (III). Novel chemical intermediates ofthe formula (II) and (III) form a further aspect of the invention.

A further aspect of the invention is a process for the preparation of acompound of formula (I) as defined herein, which process comprises:

-   (i) the reaction of a compound of the formula (II):

or a protected form thereof, with an appropriately substituted aldehydeor ketone; or

-   (ii) the reaction of a compound of the formula (II):

or a protected form thereof, with hydrazine hydrate and then cyclising;or

-   (iii) the reaction of a compound of the formula (III):

or a protected form thereof, wherein Y is a groups which can beconverted to an amide e.g. methyl, carboxylic acid, carboxylic ester,halide;

-   -   and then converting to an amide;    -   and thereafter removing any protecting group present;    -   wherein X₁₋₅, A, B, R¹ and R² are as defined herein; and        optionally thereafter converting one compound of the formula (I)        into another compound of the formula (I).

According to a further aspect of the invention there is provided a novelintermediate as defined herein.

Pharmaceutically Acceptable Salts, Solvates or Derivatives thereof.

In this section, as in all other sections of this application, unlessthe context indicates otherwise, references to formula (I) includereferences to all other sub-groups, preferences and examples thereof asdefined herein.

Unless otherwise specified, a reference to a particular compound alsoincludes ionic forms, salts, solvates, isomers, tautomers, N-oxides,esters, prodrugs, isotopes and protected forms thereof, for example, asdiscussed below; preferably, the ionic forms, or salts or tautomers orisomers or N-oxides or solvates thereof; and more preferably, the ionicforms, or salts or tautomers or solvates or protected forms thereof.Many compounds of the formula (I) can exist in the form of salts, forexample acid addition salts or, in certain cases salts of organic andinorganic bases such as carboxylate, sulphonate and phosphate salts. Allsuch salts are within the scope of this invention, and references tocompounds of the formula (I) include the salt forms of the compounds.

The salts of the present invention can be synthesized from the parentcompound that contains a basic or acidic moiety by conventional chemicalmethods such as methods described in Pharmaceutical Salts: Properties,Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth(Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002.Generally, such salts can be prepared by reacting the free acid or baseforms of these compounds with the appropriate base or acid in water orin an organic solvent, or in a mixture of the two; generally, nonaqueousmedia such as ether, ethyl acetate, ethanol, isopropanol, oracetonitrile are used.

Acid addition salts may be formed with a wide variety of acids, bothinorganic and organic. Examples of acid addition salts include saltsformed with an acid selected from the group consisting of acetic,2,2-dichloroacetic, adipic, alginic, ascorbic (e.g. L-ascorbic),L-aspartic, benzenesulphonic, benzoic, 4-acetamidobenzoic, butanoic, (+)camphoric, camphor-sulphonic, (+)-(1S)-camphor-10-sulphonic, capric,caproic, caprylic, cinnamic, citric, cyclamic, dodecylsulphuric,ethane-1,2-disulphonic, ethanesulphonic, 2-hydroxyethanesulphonic,formic, fumaric, galactaric, gentisic, glucoheptonic, D-gluconic,glucuronic (e.g. D-glucuronic), glutamic (e.g. L-glutamic),α-oxoglutaric, glycolic, hippuric, hydrobromic, hydrochloric, hydriodic,isethionic, lactic (e.g. (+)-L-lactic, (±)-DL-lactic), lactobionic,maleic, malic, (−)-L-malic, malonic, (±)-DL-mandelic, methanesulphonic,naphthalenesulphonic (e.g. naphthalene-2-sulphonic),naphthalene-1,5-disulphonic, 1-hydroxy-2-naphthoic, nicotinic, nitric,oleic, orotic, oxalic, palmitic, pamoic, phosphoric, propionic,L-pyroglutamic, salicylic, 4-amino-salicylic, sebacic, stearic,succinic, sulphuric, tannic, (+)-L-tartaric, thiocyanic,toluenesulphonic (e.g. p-toluenesulphonic), undecylenic and valericacids, as well as acylated amino acids and cation exchange resins.

One particular group of salts consists of salts formed from acetic,hydrochloric, hydriodic, phosphoric, nitric, sulphuric, citric, lactic,succinic, maleic, malic, isethionic, fumaric, benzenesulphonic,toluenesulphonic, methanesulphonic (mesylate), ethanesulphonic,naphthalenesulphonic, valeric, acetic, propanoic, butanoic, malonic,glucuronic and lactobionic acids.

Another group of acid addition salts includes salts formed from acetic,adipic, ascorbic, aspartic, citric, DL-Lactic, fumaric, gluconic,glucuronic, hippuric, hydrochloric, glutamic, DL-malic,methanesulphonic, sebacic, stearic, succinic and tartaric acids.

The compounds of the invention may exist as mono- or di-salts dependingupon the pKa of the acid from which the salt is formed.

If the compound is anionic, or has a functional group which may beanionic (e.g., —COOH may be —COO⁻), then a salt may be formed with asuitable cation. Examples of suitable inorganic cations include, but arenot limited to, alkali metal ions such as Na⁺ and K⁺, alkaline earthmetal cations such as Ca²⁺ and Mg²⁺, and other cations such as Al³⁺.Examples of suitable organic cations include, but are not limited to,ammonium ion (i.e., NH₄ ⁺) and substituted ammonium ions (e.g., NH₃R⁺,NH₂R₂ ⁺, NHR₃ ⁺, NR₄ ⁺).

Examples of some suitable substituted ammonium ions are those derivedfrom: ethylamine, diethylamine, dicyclohexylamine, triethylamine,butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine,benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, aswell as amino acids, such as lysine and arginine. An example of a commonquaternary ammonium ion is N(CH₃)₄ ⁺.

Where the compounds of the formula (I) contain an amine function, thesemay form quaternary ammonium salts, for example by reaction with analkylating agent according to methods well known to the skilled person.Such quaternary ammonium compounds are within the scope of formula (I).

The salt forms of the compounds of the invention are typicallypharmaceutically acceptable salts, and examples of pharmaceuticallyacceptable salts are discussed in Berge et al. (1977), “PharmaceuticallyAcceptable Salts,” J. Pharm. Sci., Vol. 66, pp. 1-19. However, saltsthat are not pharmaceutically acceptable may also be prepared asintermediate forms which may then be converted into pharmaceuticallyacceptable salts. Such non-pharmaceutically acceptable salts forms,which may be useful, for example, in the purification or separation ofthe compounds of the invention, also form part of the invention.

Compounds of the formula (I) containing an amine function may also formN-oxides. A reference herein to a compound of the formula (I) thatcontains an amine function also includes the N-oxide.

Where a compound contains several amine functions, one or more than onenitrogen atom may be oxidised to form an N-oxide. Particular examples ofN-oxides are the N-oxides of a tertiary amine or a nitrogen atom of anitrogen-containing heterocycle.

N-Oxides can be formed by treatment of the corresponding amine with anoxidizing agent such as hydrogen peroxide or a per-acid (e.g. aperoxycarboxylic acid), see for example Advanced Organic Chemistry, byJerry March, 4th Edition, Wiley Interscience, pages. More particularly,N-oxides can be made by the procedure of Deady, L. W. (Syn. Comm.(1977), 7, 509-514) in which the amine compound is reacted withm-chloroperoxybenzoic acid (MCPBA), for example, in an inert solventsuch as dichloromethane.

The compounds of the invention may form solvates, for example with water(i.e., hydrates) or common organic solvents. As used herein, the term“solvate” means a physical association of the compounds of the presentinvention with one or more solvent molecules. This physical associationinvolves varying degrees of ionic and covalent bonding, includinghydrogen bonding. In certain instances the solvate will be capable ofisolation, for example when one or more solvent molecules areincorporated in the crystal lattice of the crystalline solid. The term“solvate” is intended to encompass both solution-phase and isolatablesolvates. Non-limiting examples of suitable solvates include compoundson the invention in combination with water, isopropanol, ethanol,methanol, DMSO, ethyl acetate, acetic acid or ethanolamine and the like.The compounds of the invention may exert their biological effects whilstthey are in solution.

Solvates are well known in pharmaceutical chemistry. They can beimportant to the processes for the preparation of a substance (e.g. inrelation to their purification, the storage of the substance (e.g. itsstability) and the ease of handling of the substance and are oftenformed as part of the isolation or purification stages of a chemicalsynthesis. A person skilled in the art can determine by means ofstandard and long used techniques whether a hydrate or other solvate hasformed by the isolation conditions or purification conditions used toprepare a given compound. Examples of such techniques includethermogravimetric analysis (TGA), differential scanning calorimetry(DSC), X-ray crystallography (e.g. single crystal X-ray crystallographyor X-ray powder diffraction) and Solid State NMR (SS-NMR, also known asMagic Angle Spinning NMR or MAS-NMR). Such techniques are as much a partof the standard analytical toolkit of the skilled chemist as NMR, IR,HPLC and MS.

Alternatively the skilled person can deliberately form a solvate usingcrystallisation using crystallisation conditions that include an amountof the solvent required for the particular solvate. Thereafter thestandard methods described above, can be used to establish whethersolvates had formed.

Furthermore, the compounds of the present invention may have one or morepolymorph, amorphous or crystalline forms and as such are intended to beincluded in the scope of the invention.

Compounds of the formula (I) may exist in a number of differentgeometric isomeric, and tautomeric forms and references to compounds ofthe formula (I) include all such forms. For the avoidance of doubt,where a compound can exist in one of several geometric isomeric ortautomeric forms and only one is specifically described or shown, allothers are nevertheless embraced by formula (I).

Other examples of tautomeric forms include, for example, keto-, enol-,and enolate-forms, as in, for example, the following tautomeric pairs:keto/enol (illustrated below), imine/enamine, amide/imino alcohol,amidine/amidine, nitroso/oxime, thioketone/enethiol, andnitro/aci-nitro.

Where compounds of the formula (I) contain one or more chiral centres,and can exist in the form of two or more optical isomers, references tocompounds of the formula (I) include all optical isomeric forms thereof(e.g. enantiomers, epimers and diastereoisomers), either as individualoptical isomers, or mixtures (e.g. racemic mixtures) or two or moreoptical isomers, unless the context requires otherwise.

The optical isomers may be characterised and identified by their opticalactivity (i.e. as + and − isomers, or d and l isomers) or they may becharacterised in terms of their absolute stereochemistry using the “Rand S” nomenclature developed by Cahn, Ingold and Prelog, see AdvancedOrganic Chemistry by Jerry March, 4^(th) Edition, John Wiley & Sons, NewYork, 1992, pages 109-114, and see also Cahn, Ingold & Prelog (1966),Angew. Chem. Int. Ed. Engl., 5, 385-415.

Optical isomers can be separated by a number of techniques includingchiral chromatography (chromatography on a chiral support) and suchtechniques are well known to the person skilled in the art.

As an alternative to chiral chromatography, optical isomers can beseparated by forming diastereoisomeric salts with chiral acids such as(+)-tartaric acid, (−)-pyroglutamic acid, (−)-di-toluoyl-L-tartaricacid, (+)-mandelic acid, (−)-malic acid, and (−)-camphorsulphonic,separating the diastereoisomers by preferential crystallisation, andthen dissociating the salts to give the individual enantiomer of thefree base.

Where compounds of the formula (I) exist as two or more optical isomericforms, one enantiomer in a pair of enantiomers may exhibit advantagesover the other enantiomer, for example, in terms of biological activity.Thus, in certain circumstances, it may be desirable to use as atherapeutic agent only one of a pair of enantiomers, or only one of aplurality of diastereoisomers. Accordingly, the invention providescompositions containing a compound of the formula (I) having one or morechiral centres, wherein at least 55% (e.g. at least 60%, 65%, 70%, 75%,80%, 85%, 90% or 95%) of the compound of the formula (I) is present as asingle optical isomer (e.g. enantiomer or diastereoisomer). In onegeneral embodiment, 99% or more (e.g. substantially all) of the totalamount of the compound of the formula (I) may be present as a singleoptical isomer (e.g. enantiomer or diastereoisomer).

The compounds of the invention include compounds with one or moreisotopic substitutions, and a reference to a particular element includeswithin its scope all isotopes of the element. For example, a referenceto hydrogen includes within its scope ¹H, ²H (D), and ³H (T). Similarly,references to carbon and oxygen include within their scope respectively¹²C, ¹³C and ¹⁴C and ¹⁶O and ¹⁸O.

The isotopes may be radioactive or non-radioactive. In one embodiment ofthe invention, the compounds contain no radioactive isotopes. Suchcompounds are preferred for therapeutic use. In another embodiment,however, the compound may contain one or more radioisotopes. Compoundscontaining such radioisotopes may be useful in a diagnostic context.

Esters such as carboxylic acid esters and acyloxy esters of thecompounds of formula (I) bearing a carboxylic acid group or a hydroxylgroup are also embraced by formula (I). In one embodiment of theinvention, formula (I) includes within its scope esters of compounds ofthe formula (I) bearing a carboxylic acid group or a hydroxyl group. Inanother embodiment of the invention, formula (I) does not include withinits scope esters of compounds of the formula (I) bearing a carboxylicacid group or a hydroxyl group. Examples of esters are compoundscontaining the group —C(═O)OR, wherein R is an ester substituent, forexample, a C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀ arylgroup, preferably a C₁₋₇ alkyl group. Particular examples of estergroups include, but are not limited to, —C(═O)OCH₃, —C(═O)OCH₂CH₃,—C(═O)OC(CH₃)₃, and —C(═O)OPh. Examples of acyloxy (reverse ester)groups are represented by —OC(═O)R, wherein R is an acyloxy substituent,for example, a C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀aryl group, preferably a C₁₋₇ alkyl group. Particular examples ofacyloxy groups include, but are not limited to, —OC(═O)CH₃ (acetoxy),—OC(═O)CH₂CH₃, —OC(═O)C(CH₃)₃, —OC(═O)Ph, and —OC(═O)CH₂Ph.

Also encompassed by formula (I) are any polymorphic forms of thecompounds, solvates (e.g. hydrates), complexes (e.g. inclusion complexesor clathrates with compounds such as cyclodextrins, or complexes withmetals) of the compounds, and prodrugs of the compounds. By “prodrugs”is meant for example any compound that is converted in vivo into abiologically active compound of the formula (I).

For example, some prodrugs are esters of the active compound (e.g., aphysiologically acceptable metabolically labile ester). Duringmetabolism, the ester group (—C(═O)OR) is cleaved to yield the activedrug. Such esters may be formed by esterification, for example, of anyof the carboxylic acid groups (—C(═O)OH) in the parent compound, with,where appropriate, prior protection of any other reactive groups presentin the parent compound, followed by deprotection if required.

Examples of such metabolically labile esters include those of theformula —C(═O)OR wherein R is:

-   C₁₋₇alkyl (e.g., -Me, -Et, -nPr, -iPr, -nBu, -sBu, -iBu, -tBu);-   C₁₋₇aminoalkyl (e.g., aminoethyl; 2-(N,N-diethylamino)ethyl;    2-(4-morpholino)ethyl); and-   acyloxy-C₁₋₇alkyl (e.g., acyloxymethyl; acyloxyethyl;    pivaloyloxymethyl; acetoxymethyl; 1-acetoxyethyl;    1-(1-methoxy-1-methyl)ethyl-carbonyloxyethyl; 1-(benzoyloxy)ethyl;    isopropoxy-carbonyloxymethyl; 1-isopropoxy-carbonyloxyethyl;    cyclohexyl-carbonyloxymethyl; 1-cyclohexyl-carbonyloxyethyl;    cyclohexyloxy-carbonyloxymethyl; 1-cyclohexyloxy-carbonyloxyethyl;    (4-tetrahydropyranyloxy) carbonyloxymethyl;    1-(4-tetrahydropyranyloxy)carbonyloxyethyl;    (4-tetrahydropyranyl)carbonyloxymethyl; and    1-(4-tetrahydropyranyl)carbonyloxyethyl).

Also, some prodrugs are activated enzymatically to yield the activecompound, or a compound which, upon further chemical reaction, yieldsthe active compound (for example, as in antigen-directed enzyme pro-drugtherapy (ADEPT), gene-directed enzyme pro-drug therapy (GDEPT) andligand-directed enzyme pro-drug therapy (LIDEPT) etc.). For example, theprodrug may be a sugar derivative or other glycoside conjugate, or maybe an amino acid ester derivative.

It will be appreciated that references to “derivatives” includereferences to ionic forms, salts, solvates, isomers, tautomers,N-oxides, esters, prodrugs, isotopes and protected forms thereof.

According to one aspect of the invention there is provided a compound asdefined herein or a salt, tautomer, N-oxide or solvate thereof.

According to a further aspect of the invention there is provided acompound as defined herein or a salt or solvate thereof.

References to compounds of the formula (I), (Ia), (Ib), (Ic) and (Id)and sub-groups thereof as defined herein include within their scope thesalts or solvates or tautomers or N-oxides of the compounds.

Protein Tyrosine Kinases (PTK)

The compounds of the invention described herein inhibit or modulate theactivity of certain tyrosine kinases, and thus the compounds will beuseful in the treatment or prophylaxis of disease states or conditionsmediated by those tyrosine kinases in particular FGFR.

FGFR

The fibroblast growth factor (FGF) family of protein tyrosine kinase(PTK) receptors regulates a diverse array of physiologic functionsincluding mitogenesis, wound healing, cell differentiation andangiogenesis, and development. Both normal and malignant cell growth aswell as proliferation are affected by changes in local concentration ofFGFs, extracellular signalling molecules which act as autocrine as wellas paracrine factors. Autocrine FGF signalling may be particularlyimportant in the progression of steroid hormone-dependent cancers to ahormone independent state (Powers, et al. (2000), Endocr. Relat. Cancer,7, 165-197).

FGFs and their receptors are expressed at increased levels in severaltissues and cell lines and overexpression is believed to contribute tothe malignant phenotype. Furthermore, a number of oncogenes arehomologues of genes encoding growth factor receptors, and there is apotential for aberrant activation of FGF-dependent signalling in humanpancreatic cancer (Ozawa, et al. (2001), Teratog. Carcinog. Mutagen.,21, 27-44).

The two prototypic members are acidic fibroblast growth factor (aFGF orFGF1) and basic fibroblast growth factor (bFGF or FGF2), and to date, atleast twenty distinct FGF family members have been identified. Thecellular response to FGFs is transmitted via four types of high affinitytransmembrane protein tyrosine-kinase fibroblast growth factor receptors(FGFR) numbered 1 to 4 (FGFR1 to FGFR4). Upon ligand binding, thereceptors dimerize and auto- or trans-phosphorylate specific cytoplasmictyrosine residues to transmit an intracellular signal that ultimatelyregulates nuclear transcription factor effectors.

Disruption of the FGFR1 pathway should affect tumor cell proliferationsince this kinase is activated in many tumor types in addition toproliferating endothelial cells. The over-expression and activation ofFGFR1 in tumor-associated vasculature has suggested a role for thesemolecules in tumor angiogenesis.

Fibroblast growth factor receptor 2 has high affinity for the acidicand/or basic fibroblast growth factors, as well as the keratinocytegrowth factor ligands. Fibroblast growth factor receptor 2 alsopropagates the potent osteogenic effects of FGFs during osteoblastgrowth and differentiation. Mutations in fibroblast growth factorreceptor 2, leading to complex functional alterations, were shown toinduce abnormal ossification of cranial sutures (craniosynostosis),implying a major role of FGFR signalling in intramembraneous boneformation. For example, in Apert (AP) syndrome, characterized bypremature cranial suture ossification, most cases are associated withpoint mutations engendering gain-of-function in fibroblast growth factorreceptor 2 (Lemonnier, et al. (2001), J. Bone Miner. Res., 16, 832-845).In addition, mutation screening in patients with syndromiccraniosynostoses indicates that a number of recurrent FGFR2 mutationsaccounts for severe forms of Pfeiffer syndrome (Lajeunie et al, EuropeanJournal of Human Genetics (2006) 14, 289-298). Particular mutations ofFGFR2 include W290C, D321A, Y340C, C342R, C342S, C342W, N549H, K641R inFGFR2.

Several severe abnormalities in human skeletal development, includingApert, Crouzon, Jackson-Weiss, Beare-Stevenson cutis gyrata, andPfeiffer syndromes are associated with the occurrence of mutations infibroblast growth factor receptor 2. Most, if not all, cases of PfeifferSyndrome (PS) are also caused by de novo mutation of the fibroblastgrowth factor receptor 2 gene (Meyers, et al. (1996), Am. J. Hum.Genet., 58, 491-498; Plomp, et al. (1998), Am. J. Med. Genet., 75,245-251), and it was recently shown that mutations in fibroblast growthfactor receptor 2 break one of the cardinal rules governing ligandspecificity. Namely, two mutant splice forms of fibroblast growth factorreceptor, FGFR2c and FGFR2b, have acquired the ability to bind to and beactivated by atypical FGF ligands. This loss of ligand specificity leadsto aberrant signalling and suggests that the severe phenotypes of thesedisease syndromes result from ectopic ligand-dependent activation offibroblast growth factor receptor 2 (Yu, et al. (2000), Proc. Natl.Acad. Sci. U.S.A., 97, 14536-14541).

Genetic aberrations of the FGFR3 receptor tyrosine kinase such aschromosomal translocations or point mutations result in ectopicallyexpressed or deregulated, constitutively active, FGFR3 receptors. Suchabnormalities are linked to a subset of multiple myelomas and inbladder, hepatocellular, oral squamous cell carcinoma and cervicalcarcinomas (Powers, C. J. (2000), et al., Endocr. Rel. Cancer, 7, 165;Qiu, W. et. al. (2005), World Journal Gastroenterol, 11(34)).Accordingly, FGFR3 inhibitors would be useful in the treatment ofmultiple myeloma, bladder and cervical carcinomas. FGFR3 is alsoover-expressed in bladder cancer, in particular invasive bladder cancer.FGFR3 is frequently activated by mutation in urothelial carcinoma (UC)(Journal of Pathology (2007), 213(1), 91-98). Increased expression wasassociated with mutation (85% of mutant tumors showed high-levelexpression) but also 42% of tumors with no detectable mutation showedover-expression, including many muscle-invasive tumors.

As such, the compounds which inhibit FGFR will be useful in providing ameans of preventing the growth or inducing apoptosis in tumours,particularly by inhibiting angiogenesis. It is therefore anticipatedthat the compounds will prove useful in treating or preventingproliferative disorders such as cancers. In particular tumours withactivating mutants of receptor tyrosine kinases or upregulation ofreceptor tyrosine kinases may be particularly sensitive to theinhibitors. Patients with activating mutants of any of the isoforms ofthe specific RTKs discussed herein may also find treatment with RTKinhibitors particularly beneficial.

Over expression of FGFR4 has been linked to poor prognosis in bothprostate and thyroid carcinomas (Ezzat, S., et al. (2002), The Journalof Clinical Investigation, 109, 1; Wang et al. (2004), Clinical CancerResearch, 10). In addition a germline polymorphism (Gly388Arg) isassociated with increased incidence of lung, breast, colon and prostatecancers (Wang et al. (2004), Clinical Cancer Research, 10). In addition,a truncated form of FGFR4 (including the kinase domain) has also beenfound to present in 40% of pituitary tumours but not present in normaltissue.

A recent study has shown a link between FGFR1 expression andtumorigenicity in Classic Lobular Carcinomas (CLC). CLCs account for10-15% of all breast cancers and, in general, lack p53 and Her2expression whilst retaining expression of the oestrogen receptor. A geneamplification of 8p12-p11.2 was demonstrated in ˜50% of CLC cases andthis was shown to be linked with an increased expression of FGFR1.Preliminary studies with siRNA directed against FGFR1, or a smallmolecule inhibitor of the receptor, showed cell lines harbouring thisamplification to be particularly sensitive to inhibition of thissignalling pathway (Reis-Filho et al. (2006), Clin Cancer Res. 12(22):6652-6662.

Rhabdomyosarcoma (RMS), the most common pediatric soft tissue sarcomalikely results from abnormal proliferation and differentiation duringskeletal myogenesis. FGFR1 is over-expressed in primary rhabdomyosarcomatumors and is associated with hypomethylation of a 5′ CpG island andabnormal expression of the AKT1, NOG, and BMP4 genes (Genes, Chromosomes& Cancer (2007), 46(11), 1028-1038).

Fibrotic conditions are a major medical problem resulting from abnormalor excessive deposition of fibrous tissue. This occurs in many diseases,including liver cirrhosis, glomerulonephritis, pulmonary fibrosis,systemic fibrosis, rheumatoid arthritis, as well as the natural processof wound healing. The mechanisms of pathological fibrosis are not fullyunderstood but are thought to result from the actions of variouscytokines (including tumor necrosis factor (TNF), fibroblast growthfactors (FGF's), platelet derived growth factor (PDGF) and transforminggrowth factor beta. (TGFβ) involved in the proliferation of fibroblastsand the deposition of extracellular matrix proteins (including collagenand fibronectin). This results in alteration of tissue structure andfunction and subsequent pathology.

A number of preclinical studies have demonstrated the up-regulation offibroblast growth factors in preclinical models of lung fibrosis (Inoue,et al., 1997 & 2002; Barrios, et al. 1997)). TGFβ1 and PDGF have beenreported to be involved in the fibrogenic process (reviewed by Atamas &White, 2003) and further published work suggests the elevation of FGF'sand consequent increase in fibroblast proliferation, may be in responseto elevated TGFβ1 (Khalil, et al., 2005). The potential therapeuticrelevance of this pathway in fibrotic conditions is suggested by thereported clinical effect of Pirfenidone (Arata, et al., 2005) inidiopathic pulmonary fibrosis (IPF). Idiopathic pulmonary fibrosis (alsoreferred to as Cryptogenic fibrosing alveolitis) is a progressivecondition involving scarring of the lung. Gradually, the air sacs of thelungs become replaced by fibrotic tissue, which becomes thicker, causingan irreversible loss of the tissue's ability to transfer oxygen into thebloodstream. The symptoms of the condition include shortness of breath,chronic dry coughing, fatigue, chest pain and loss of appetite resultingin rapid weight loss. The condition is extremely serious withapproximately 50% mortality after 5 years.

Vascular Endothelial Growth Factor (VEGFR)

Chronic proliferative diseases are often accompanied by profoundangiogenesis, which can contribute to or maintain an inflammatory and/orproliferative state, or which leads to tissue destruction through theinvasive proliferation of blood vessels. (Folkman (1997), 79, 1-81;Folkman (1995), Nature Medicine, 1, 27-31; Folkman and Shing (1992), J.Biol. Chem., 267, 10931).

Angiogenesis is generally used to describe the development of new orreplacement blood vessels, or neovascularisation. It is a necessary andphysiological normal process by which vasculature is established in theembryo. Angiogenesis does not occur, in general, in most normal adulttissues, exceptions being sites of ovulation, menses and wound healing.Many diseases, however, are characterized by persistent and unregulatedangiogenesis. For instance, in arthritis, new capillary blood vesselsinvade the joint and destroy cartilage (Colville-Nash and Scott (1992),Ann. Rhum. Dis., 51, 919). In diabetes (and in many different eyediseases), new vessels invade the macula or retina or other ocularstructures, and may cause blindness (Brooks, et al. (1994), Cell, 79,1157). The process of atherosclerosis has been linked to angiogenesis(Kahlon, et al. (1992), Can. J. Cardiol., 8, 60). Tumor growth andmetastasis have been found to be angiogenesis-dependent (Folkman (1992),Cancer Biol, 3, 65; Denekamp (1993), Br. J. Rad., 66, 181; Fidler andEllis (1994), Cell, 79, 185).

The recognition of the involvement of angiogenesis in major diseases hasbeen accompanied by research to identify and develop inhibitors ofangiogenesis. These inhibitors are generally classified in response todiscrete targets in the angiogenesis cascade, such as activation ofendothelial cells by an angiogenic signal; synthesis and release ofdegradative enzymes; endothelial cell migration; proliferation ofendothelial cells; and formation of capillary tubules. Therefore,angiogenesis occurs in many stages and attempts are underway to discoverand develop compounds that work to block angiogenesis at these variousstages.

There are publications that teach that inhibitors of angiogenesis,working by diverse mechanisms, are beneficial in diseases such as cancerand metastasis (O'Reilly, et al. (1994), Cell, 79, 315; Ingber, et al.,(1990), Nature, 348, 555), ocular diseases (Friedlander, et al. (1995),Science, 270, 1500), arthritis (Peacock, et al. (1992), J. Exp. Med.,175, 1135; Peacock et al. (1995), Cell. Immun., 160, 178) and hemangioma(Taraboletti, et al. (1995), J. Natl. Cancer Inst., 87, 293).

Receptor tyrosine kinases (RTKs) are important in the transmission ofbiochemical signals across the plasma membrane of cells. Thesetransmembrane molecules characteristically consist of an extracellularligand-binding domain connected through a segment in the plasma membraneto an intracellular tyrosine kinase domain. Binding of ligand to thereceptor results in stimulation of the receptor-associated tyrosinekinase activity that leads to phosphorylation of tyrosine residues onboth the receptor and other intracellular proteins, leading to a varietyof cellular responses. To date, at least nineteen distinct RTKsubfamilies, defined by amino acid sequence homology, have beenidentified.

Vascular endothelial growth factor (VEGF), a polypeptide, is mitogenicfor endothelial cells in vitro and stimulates angiogenic responses invivo. VEGF has also been linked to inappropriate angiogenesis (Pinedo,H. M., et al. (2000), The Oncologist, 5(90001), 1-2). VEGFR(s) areprotein tyrosine kinases (PTKs). PTKs catalyze the phosphorylation ofspecific tyrosine residues in proteins involved in cell function thusregulating cell growth, survival and differentiation. (Wilks, A. F.(1990), Progress in Growth Factor Research, 2, 97-111; Courtneidge, S.A. (1993), Dev. Supp. I, 57-64; Cooper, J. A. (1994), Semin. Cell Biol.,5(6), 377-387; Paulson, R. F. (1995), Semin. Immunol., 7(4), 267-277;Chan, A. C. (1996), Curr. Opin. Immunol., 8(3), 394-401).

Three PTK receptors for VEGF have been identified: VEGFR-1 (Flt-1);VEGFR-2 (Flk-1 or KDR) and VEGFR-3 (Flt-4). These receptors are involvedin angiogenesis and participate in signal transduction (Mustonen, T., etal. (1995), J. Cell Biol., 129, 895-898).

Of particular interest is VEGFR-2, which is a transmembrane receptor PTKexpressed primarily in endothelial cells. Activation of VEGFR-2 by VEGFis a critical step in the signal transduction pathway that initiatestumour angiogenesis. VEGF expression may be constitutive to tumour cellsand can also be upregulated in response to certain stimuli. One suchstimuli is hypoxia, where VEGF expression is upregulated in both tumourand associated host tissues. The VEGF ligand activates VEGFR-2 bybinding with its extracellular VEGF binding site. This leads to receptordimerization of VEGFRs and autophosphorylation of tyrosine residues atthe intracellular kinase domain of VEGFR-2. The kinase domain operatesto transfer a phosphate from ATP to the tyrosine residues, thusproviding binding sites for signalling proteins downstream of VEGFR-2leading ultimately to initiation of angiogenesis (McMahon, G. (2000),The Oncologist, 5(90001), 3-10).

Inhibition at the kinase domain binding site of VEGFR-2 would blockphosphorylation of tyrosine residues and serve to disrupt initiation ofangiogenesis.

Angiogenesis is a physiologic process of new blood vessel formationmediated by various cytokines called angiogenic factors. Although itspotential pathophysiologic role in solid tumors has been extensivelystudied for more than 3 decades, enhancement of angiogenesis in chroniclymphocytic leukemia (CLL) and other malignant hematological disordershas been recognized more recently. An increased level of angiogenesishas been documented by various experimental methods both in bone marrowand lymph nodes of patients with CLL. Although the role of angiogenesisin the pathophysiology of this disease remains to be fully elucidated,experimental data suggest that several angiogenic factors play a role inthe disease progression. Biologic markers of angiogenesis were alsoshown to be of prognostic relevance in CLL. This indicates that VEGFRinhibitors may also be of benefit for patients with leukemia's such asCLL.

In order for a tumour mass to get beyond a critical size, it mustdevelop an associated vasculature. It has been proposed that targeting atumor vasculature would limit tumor expansion and could be a usefulcancer therapy. Observations of tumor growth have indicated that smalltumour masses can persist in a tissue without any tumour-specificvasculature. The growth arrest of nonvascularized tumors has beenattributed to the effects of hypoxia at the center of the tumor. Morerecently, a variety of proangiogenic and antiangiogenic factors havebeen identified and have led to the concept of the “angiogenic switch,”a process in which disruption of the normal ratio of angiogenic stimuliand inhibitors in a tumor mass allows for autonomous vascularization.The angiogenic switch appears to be governed by the same geneticalterations that drive malignant conversion: the activation of oncogenesand the loss of tumour suppressor genes. Several growth factors act aspositive regulators of angiogenesis. Foremost among these are vascularendothelial growth factor (VEGF), basic fibroblast growth factor (bFGF),and angiogenin. Proteins such as thrombospondin (Tsp-1), angiostatin,and endostatin function as negative regulators of angiogenesis.

Inhibition of VEGFR2 but not VEGFR1 markedly disrupts angiogenicswitching, persistent angiogenesis, and initial tumor growth in a mousemodel. In late-stage tumors, phenotypic resistance to VEGFR2 blockadeemerged, as tumors regrew during treatment after an initial period ofgrowth suppression. This resistance to VEGF blockade involvesreactivation of tumour angiogenesis, independent of VEGF and associatedwith hypoxia-mediated induction of other proangiogenic factors,including members of the FGF family. These other proangiogenic signalsare functionally implicated in the revascularization and regrowth oftumours in the evasion phase, as FGF blockade impairs progression in theface of VEGF inhibition. Inhibition of VEGFR2 but not VEGFR1 markedlydisrupted angiogenic switching, persistent angiogenesis, and initialtumor growth. In late-stage tumours, phenotypic resistance to VEGFR2blockade emerged, as tumours regrew during treatment after an initialperiod of growth suppression. This resistance to VEGF blockade involvesreactivation of tumour angiogenesis, independent of VEGF and associatedwith hypoxia-mediated induction of other proangiogenic factors,including members of the FGF family. These other proangiogenic signalsare functionally implicated in the revascularization and regrowth oftumours in the evasion phase, as FGF blockade impairs progression in theface of VEGF inhibition.

A FGF-trap adenovirus has been previously reported to bind and blockvarious ligands of the FGF family, including FGF1, FGF3, FGF7, andFGF10, thereby effectively inhibiting angiogenesis in vitro and in vivo.Indeed, adding the FGF-trap treatment in the regrowth phase of a mousemodel produced a significant decrease in tumor growth compared toanti-VEGFR2 alone. This decrease in tumor burden was accompanied by adecrease in angiogenesis that was observed as decreased intratumoralvessel density.

Batchelor et al. (Batchelor et al., 2007, Cancer Cell, 11(1), 83-95)provide evidence for normalization of glioblastoma blood vessels inpatients treated with a pan-VEGF receptor tyrosine kinase inhibitor,AZD2171, in a phase 2 study. The rationale for using AZD2171 was basedpartially on results showing a decrease in perfusion and vessel densityin an in vivo breast cancer model (Miller et al., 2006, Clin. CancerRes. 12, 281-288). Furthermore, using an orthotopic glioma model, it hadpreviously been identified that the optimal window of time to deliveranti-VEGFR2 antibody to achieve a synergistic effect with radiation.During the window of normalization, there was improved oxygenation,increased pericyte coverage, and upregulation of angiopoietin-1 leadingto a decrease in interstitial pressure and permeability within thetumour (Winkler et al., 2004, Cancer Cell 6, 553-563). The window ofnormalization can be quantified using magnetic resonance imaging (MRI)using MRI gradient echo, spin echo, and contrast enhancement to measureblood volume, relative vessel size, and vascular permeability.

The authors showed that progression on treatment with AZD2171 wasassociated with an increase in CECs, SDF1, and FGF2, while progressionafter drug interruptions correlated with increases in circulatingprogenitor cells (CPCs) and plasma FGF2 levels. The increase in plasmalevels of SDF1 and FGF2 correlated with MRI measurements, demonstratedan increase in the relative vessel density and size. Thus, MRIdetermination of vessel normalization in combination with circulatingbiomarkers provides for an effective means to assess response toantiangiogenic agents.

PDGFR

A malignant tumour is the product of uncontrolled cell proliferation.Cell growth is controlled by a delicate balance between growth-promotingand growth-inhibiting factors. In normal tissue the production andactivity of these factors results in differentiated cells growing in acontrolled and regulated manner that maintains the normal integrity andfunctioning of the organ. The malignant cell has evaded this control;the natural balance is disturbed (via a variety of mechanisms) andunregulated, aberrant cell growth occurs. A growth factor of importancein tumour development is the platelet-derived growth factor (PDGF) thatcomprises a family of peptide growth factors that signal through cellsurface tyrosine kinase receptors (PDGFR) and stimulate various cellularfunctions including growth, proliferation, and differentiation. PDGFexpression has been demonstrated in a number of different solid tumoursincluding glioblastomas and prostate carcinomas. The tyrosine kinaseinhibitor imatinib mesylate, which has the chemical name4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-ylpyridinyl]amino]-phenyl]benzamidemethanesulfonate, blocks activity of the Bcr-Abl oncoprotein and thecell surface tyrosine kinase receptor c-Kit, and as such is approved forthe treatment of chronic myeloid leukemia and gastrointestinal stromaltumours. Imatinib mesylate is also a potent inhibitor of PDGFR kinaseand is currently being evaluated for the treatment of chronicmyelomonocytic leukemia and glioblastoma multiforme, based upon evidencein these diseases of activating mutations in PDGFR. In addition,sorafenib (BAY 43-9006) which has the chemical name4-(4-(3-(4-chloro-3(trifluoromethyl)phenyl)ureido)phenoxy)-N2-methylpyridine-2-carboxamide, targets both the Rafsignalling pathway to inhibit cell proliferation and the VEGFR/PDGFRsignalling cascades to inhibit tumour angiogenesis. Sorafenib is beinginvestigated for the treatment of a number of cancers including liverand kidney cancer.

There are conditions which are dependent on activation of PDGFR such ashypereosinophilic syndrome. PDGFR activation is also associated withother malignancies, which include chronic myelomonocytic leukemia(CMML). In another disorder, dermatofibrosarcoma protuberans, aninfiltrative skin tumor, a reciprocal translocation involving the geneencoding the PDGF-B ligand results in constitutive secretion of thechimeric ligand and receptor activation. Imatinib has which is a knowninhibitor of PDGFR has activity against all three of these diseases.

Advantages of a Selective Inhibitor

Development of FGFR kinase inhibitors with a differentiated selectivityprofile provides a new opportunity to use these targeted agents inpatient sub-groups whose disease is driven by FGFR deregulation.Compounds that exhibit reduced inhibitory action on additional kinases,particularly VEGFR2 and PDGFR-beta, offer the opportunity to have adifferentiated side-effect or toxicity profile and as such allow for amore effective treatment of these indications. Inhibitors of VEGFR2 andPDGFR-beta are associated with toxicities such as hypertension or oedemarespectively. In the case of VEGFR2 inhibitors this hypertensive effectis often dose limiting, may be contraindicated in certain patientpopulations and requires clinical management.

Biological Activity and Therapeutic Uses

The compounds of the invention, and subgroups thereof, have fibroblastgrowth factor receptor (FGFR) inhibiting or modulating activity and/orvascular endothelial growth factor receptor (VEGFR) inhibiting ormodulating activity, and/or platelet derived growth factor receptor(PDGFR) inhibiting or modulating activity, and which will be useful inpreventing or treating disease states or conditions described herein. Inaddition the compounds of the invention, and subgroups thereof, will beuseful in preventing or treating diseases or condition mediated by thekinases. References to the preventing or prophylaxis or treatment of adisease state or condition such as cancer include within their scopealleviating or reducing the incidence of cancer.

As used herein, the term “modulation”, as applied to the activity of akinase, is intended to define a change in the level of biologicalactivity of the protein kinase. Thus, modulation encompassesphysiological changes which effect an increase or decrease in therelevant protein kinase activity. In the latter case, the modulation maybe described as “inhibition”. The modulation may arise directly orindirectly, and may be mediated by any mechanism and at anyphysiological level, including for example at the level of geneexpression (including for example transcription, translation and/orpost-translational modification), at the level of expression of genesencoding regulatory elements which act directly or indirectly on thelevels of kinase activity. Thus, modulation may implyelevated/suppressed expression or over- or under-expression of a kinase,including gene amplification (i.e. multiple gene copies) and/orincreased or decreased expression by a transcriptional effect, as wellas hyper- (or hypo-)activity and (de)activation of the protein kinase(s)(including (de)activation) by mutation(s). The terms “modulated”,“modulating” and “modulate” are to be interpreted accordingly.

As used herein, the term “mediated”, as used e.g. in conjunction with akinase as described herein (and applied for example to variousphysiological processes, diseases, states, conditions, therapies,treatments or interventions) is intended to operate limitatively so thatthe various processes, diseases, states, conditions, treatments andinterventions to which the term is applied are those in which the kinaseplays a biological role. In cases where the term is applied to adisease, state or condition, the biological role played by a kinase maybe direct or indirect and may be necessary and/or sufficient for themanifestation of the symptoms of the disease, state or condition (or itsaetiology or progression). Thus, kinase activity (and in particularaberrant levels of kinase activity, e.g. kinase over-expression) neednot necessarily be the proximal cause of the disease, state orcondition: rather, it is contemplated that the kinase mediated diseases,states or conditions include those having multifactorial aetiologies andcomplex progressions in which the kinase in question is only partiallyinvolved. In cases where the term is applied to treatment, prophylaxisor intervention, the role played by the kinase may be direct or indirectand may be necessary and/or sufficient for the operation of thetreatment, prophylaxis or outcome of the intervention. Thus, a diseasestate or condition mediated by a kinase includes the development ofresistance to any particular cancer drug or treatment.

Thus, for example, it is envisaged that the compounds of the inventionwill be useful in alleviating or reducing the incidence of cancer.

More particularly, the compounds of the formulae (I) and sub-groupsthereof are inhibitors of FGFRs. For example, compounds of the inventionhave activity against FGFR1, FGFR2, FGFR3, and/or FGFR4, and inparticular FGFRs selected from FGFR1, FGFR2 and FGFR3.

Preferred compounds are compounds that inhibit one or more FGFR selectedfrom FGFR1, FGFR2 and FGFR3, and also FGFR4. Preferred compounds of theinvention are those having IC₅₀ values of less than 0.1 μM.

Compounds of the invention also have activity against VEGFR.

Compounds of the invention also have activity against PDGFR kinases. Inparticular, the compounds are inhibitors of PDGFR and, for example,inhibit PDGFR A and/or PDGFR B.

In addition many of the compounds of the invention exhibit selectivityfor the FGFR1, 2, and/or 3 kinase, and/or FGFR4 compared to VEGFR (inparticular VEGFR2) and/or PDGFR and such compounds represent onepreferred embodiment of the invention. In particular, the compoundsexhibit selectivity over VEGFR2. For example, many compounds of theinvention have IC₅₀ values against FGFR1, 2 and/or 3 and/or FGFR4 thatare between a tenth and a hundredth of the IC₅₀ against VEGFR (inparticular VEGFR2) and/or PDGFR B. In particular preferred compounds ofthe invention have at least 10 times greater activity against orinhibition of FGFR in particular FGFR1, FGFR2, FGFR3 and/or FGFR4 thanVEGFR2. More preferably the compounds of the invention have at least 100times greater activity against or inhibition of FGFR in particularFGFR1, FGFR2, FGFR3 and/or FGFR4 than VEGFR2. This can be determinedusing the methods described herein.

As a consequence of their activity in modulating or inhibiting FGFR,VEGFR and/or PDGFR kinases, the compounds will be useful in providing ameans of preventing the growth or inducing apoptosis of neoplasias,particularly by inhibiting angiogenesis. It is therefore anticipatedthat the compounds will prove useful in treating or preventingproliferative disorders such as cancers. In addition, the compounds ofthe invention could be useful in the treatment of diseases in whichthere is a disorder of proliferation, apoptosis or differentiation.

In particular tumours with activating mutants of VEGFR or upregulationof VEGFR and patients with elevated levels of serum lactatedehydrogenase may be particularly sensitive to the compounds of theinvention. Patients with activating mutants of any of the isoforms ofthe specific RTKs discussed herein may also find treatment with thecompounds of the invention particularly beneficial. For example, VEGFRoverexpression in acute leukemia cells where the clonal progenitor mayexpress VEGFR. Also, particular tumours with activating mutants orupregulation or overexpression of any of the isoforms of FGFR such asFGFR1, FGFR2 or FGFR3 or FGFR4 may be particularly sensitive to thecompounds of the invention and thus patients as discussed herein withsuch particular tumours may also find treatment with the compounds ofthe invention particularly beneficial. It may be preferred that thetreatment is related to or directed at a mutated form of one of thereceptor tyrosine kinases, such as discussed herein. Diagnosis oftumours with such mutations could be performed using techniques known toa person skilled in the art and as described herein such as RTPCR andFISH.

Examples of cancers which may be treated (or inhibited) include, but arenot limited to, a carcinoma, for example a carcinoma of the bladder,breast, colon (e.g. colorectal carcinomas such as colon adenocarcinomaand colon adenoma), kidney, epidermis, liver, lung, for exampleadenocarcinoma, small cell lung cancer and non-small cell lungcarcinomas, esophagus, gall bladder, ovary, pancreas e.g. exocrinepancreatic carcinoma, stomach, cervix, endometrium, thyroid, prostate,or skin, for example squamous cell carcinoma; a hematopoietic tumour oflymphoid lineage, for example leukemia, acute lymphocytic leukemia,chronic lymphocytic leukemia, B-cell lymphoma, T-cell lymphoma,Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, orBurkett's lymphoma; a hematopoietic tumour of myeloid lineage, forexample leukemias, acute and chronic myelogenous leukemias,myeloproliferative syndrome, myelodysplastic syndrome, or promyelocyticleukemia; multiple myeloma; thyroid follicular cancer; a tumour ofmesenchymal origin, for example fibrosarcoma or rhabdomyosarcoma; atumour of the central or peripheral nervous system, for exampleastrocytoma, neuroblastoma, glioma or schwannoma; melanoma; seminoma;teratocarcinoma; osteosarcoma; xeroderma pigmentosum; keratoctanthoma;thyroid follicular cancer; or Kaposi's sarcoma.

Certain cancers are resistant to treatment with particular drugs. Thiscan be due to the type of the tumour or can arise due to treatment withthe compound. In this regard, references to multiple myeloma includesbortezomib sensitive multiple myeloma or refractory multiple myeloma.Similarly, references to chronic myelogenous leukemia includes imatinibsensitive chronic myelogenous leukemia and refractory chronicmyelogenous leukemia. Chronic myelogenous leukemia is also known aschronic myeloid leukemia, chronic granulocytic leukemia or CML.Likewise, acute myelogenous leukemia, is also called acute myeloblasticleukemia, acute granulocytic leukemia, acute nonlymphocytic leukaemia orAML.

The compounds of the invention can also be used in the treatment ofhematopoetic diseases of abnormal cell proliferation whetherpre-malignant or stable such as myeloproliferative diseases.Myeloproliferative diseases (“MPD”s) are a group of diseases of the bonemarrow in which excess cells are produced. They are related to, and mayevolve into, myelodysplastic syndrome. Myeloproliferative diseasesinclude polycythemia vera, essential thrombocythemia and primarymyelofibrosis.

Thus, in the pharmaceutical compositions, uses or methods of thisinvention for treating a disease or condition comprising abnormal cellgrowth, the disease or condition comprising abnormal cell growth in oneembodiment is a cancer.

Further T-cell lymphoproliferative diseases include those derived fromnatural Killer cells. The term B-cell lymphoma includes diffuse largeB-cell lymphoma.

In addition the compounds of the invention can be used togastrointestinal (also known as gastric) cancer e.g. gastrointestinalstromal tumours. Gastrointestinal cancer refers to malignant conditionsof the gastrointestinal tract, including the esophagus, stomach, liver,biliary system, pancreas, bowels, and anus.

A further example of a tumour of mesenchymal origin is Ewing's sarcoma.

Thus, in the pharmaceutical compositions, uses or methods of thisinvention for treating a disease or condition comprising abnormal cellgrowth, the disease or condition comprising abnormal cell growth in oneembodiment is a cancer.

Particular subsets of cancers include multiple myeloma, bladder,cervical, prostate and thyroid carcinomas, lung, breast, and coloncancers.

A further subset of cancers includes multiple myeloma, bladder,hepatocellular, oral squamous cell carcinoma and cervical carcinomas.

It is further envisaged that the compound of the invention having FGFRsuch as FGFR1 inhibitory activity, will be particularly useful in thetreatment or prevention of breast cancer in particular Classic LobularCarcinomas (CLC).

As the compounds of the invention have FGFR4 activity they will also beuseful in the treatment of prostate or pituitary cancers.

In particular the compounds of the invention as FGFR inhibitors, areuseful in the treatment of multiple myeloma, myeloproliferativedisorders, endometrial cancer, prostate cancer, bladder cancer, lungcancer, ovarian cancer, breast cancer, gastric cancer, colorectalcancer, and oral squamous cell carcinoma.

Further subsets of cancer are multiple myeloma, endometrial cancer,bladder cancer, cervical cancer, prostate cancer, lung cancer, breastcancer, colorectal cancer and thyroid carcinomas.

In particular the compounds of the invention are in the treatment ofmultiple myeloma (in particular multiple myeloma with t(4; 14)translocation or overexpressing FGFR3), prostate cancer (hormonerefractory prostrate carcinomas), endometrial cancer (in particularendometrial tumours with activating mutations in FGFR2) and breastcancer (in particular lobular breast cancer).

In particular the compounds are useful for the treatment of lobularcarcinomas such as CLC (Classic lobular carcinoma).

As the compounds have activity against FGFR3 they will be useful in thetreatment of multiple myeloma and bladder.

In particular the compounds are useful for the treatment of t(4; 14)translocation positive multiple myeloma.

As the compounds have activity against FGFR2 they will be useful in thetreatment of endometrial, ovarian, gastric and colorectal cancers. FGFR2is also overexpressed in epithelial ovarian cancer, therefore thecompounds of the invention may be specifically useful in treatingovarian cancer such as epithelial ovarian cancer.

Compounds of the invention may also be useful in the treatment oftumours pre-treated with VEGFR2 inhibitor or VEGFR2 antibody (e.g.Avastin).

In particular the compounds of the invention may be useful in thetreatment of VEGFR2-resistant tumours. VEGFR2 inhibitors and antibodiesare used in the treatment of thyroid and renal cell carcinomas,therefore the compounds of the invention may be useful in the treatmentof VEGFR2-resistant thyroid and renal cell carcinomas.

The cancers may be cancers which are sensitive to inhibition of any oneor more FGFRs selected from FGFR1, FGFR2, FGFR3, FGFR4, for example, oneor more FGFRs selected from FGFR1, FGFR2 or FGFR3.

Whether or not a particular cancer is one which is sensitive toinhibition of FGFR, VEGFR or PDGFR signalling may be determined by meansof a cell growth assay as set out below or by a method as set out in thesection headed “Methods of Diagnosis”.

It is further envisaged that the compounds of the invention, and inparticular those compounds having FGFR, VEGFR or PDGFR inhibitoryactivity, will be particularly useful in the treatment or prevention ofcancers of a type associated with or characterised by the presence ofelevated levels of FGFR, VEGFR or PDGFR, for example the cancersreferred to in this context in the introductory section of thisapplication.

It has been discovered that some FGFR inhibitors can be used incombination with other anticancer agents. For example, it may bebeneficial to combine an inhibitor that induces apoptosis with anotheragent which acts via a different mechanism to regulate cell growth thustreating two of the characteristic features of cancer development.Examples of such combinations are set out below.

It is also envisaged that the compounds of the invention will be usefulin treating other conditions which result from disorders inproliferation such as type II or non-insulin dependent diabetesmellitus, autoimmune diseases, head trauma, stroke, epilepsy,neurodegenerative diseases such as Alzheimer's, motor neuron disease,progressive supranuclear palsy, corticobasal degeneration and Pick'sdisease for example autoimmune diseases and neurodegenerative diseases.

One sub-group of disease states and conditions where it is envisagedthat the compounds of the invention will be useful consists ofinflammatory diseases, cardiovascular diseases and wound healing.

FGFR, VEGFR and PDGFR are also known to play a role in apoptosis,angiogenesis, proliferation, differentiation and transcription andtherefore the compounds of the invention could also be useful in thetreatment of the following diseases other than cancer; chronicinflammatory diseases, for example systemic lupus erythematosus,autoimmune mediated glomerulonephritis, rheumatoid arthritis, psoriasis,inflammatory bowel disease, autoimmune diabetes mellitus, Eczemahypersensitivity reactions, asthma, COPD, rhinitis, and upperrespiratory tract disease; cardiovascular diseases for example cardiachypertrophy, restenosis, atherosclerosis; neurodegenerative disorders,for example Alzheimer's disease, AIDS-related dementia, Parkinson'sdisease, amyotropic lateral sclerosis, retinitis pigmentosa, spinalmuscular atropy and cerebellar degeneration; glomerulonephritis;myelodysplastic syndromes, ischemic injury associated myocardialinfarctions, stroke and reperfusion injury, arrhythmia, atherosclerosis,toxin-induced or alcohol related liver diseases, haematologicaldiseases, for example, chronic anemia and aplastic anemia; degenerativediseases of the musculoskeletal system, for example, osteoporosis andarthritis, aspirin-sensitive rhinosinusitis, cystic fibrosis, multiplesclerosis, kidney diseases and cancer pain.

In addition, mutations of FGFR2 are associated with several severeabnormalities in human skeletal development and thus the compounds ofinvention could be useful in the treatment of abnormalities in humanskeletal development, including abnormal ossification of cranial sutures(craniosynostosis), Apert (AP) syndrome, Crouzon syndrome, Jackson-Weisssyndrome, Beare-Stevenson cutis gyrate syndrome, and Pfeiffer syndrome.

It is further envisaged that the compound of the invention having FGFRsuch as FGFR2 or FGFR3 inhibitory activity, will be particularly usefulin the treatment or prevention of the skeletal diseases. Particularskeletal diseases are achondroplasia or thanatophoric dwarfism (alsoknown as thanatophoric dysplasia).

It is further envisaged that the compound of the invention having FGFRsuch as FGFR1, FGFR2 or FGFR3 inhibitory activity, will be particularlyuseful in the treatment or prevention in pathologies in whichprogressive fibrosis is a symptom. Fibrotic conditions in which thecompounds of the inventions may be useful in the treatment of in includediseases exhibiting abnormal or excessive deposition of fibrous tissuefor example in liver cirrhosis, glomerulonephritis, pulmonary fibrosis,systemic fibrosis, rheumatoid arthritis, as well as the natural processof wound healing. In particular the compounds of the inventions may alsobe useful in the treatment of lung fibrosis in particular in idiopathicpulmonary fibrosis.

The over-expression and activation of FGFR and VEGFR in tumor-associatedvasculature has also suggested a role for compounds of the invention inpreventing and disrupting initiation of tumor angiogenesis. Inparticular the compounds of the invention may be useful in the treatmentof cancer, metastasis, leukemia's such as CLL, ocular diseases such asage-related macular degeneration in particular wet form of age-relatedmacular degeneration, ischemic proliferative retinopathies such asretinopathy of prematurity (ROP) and diabetic retinopathy, rheumatoidarthritis and hemangioma.

Since compounds of the invention inhibit PDGFR they may also be usefulin the treatment of a number of tumour and leukemia types includingglioblastomas such as glioblastoma multiforme, prostate carcinomas,gastrointestinal stromal tumours, liver cancer, kidney cancer, chronicmyeloid leukemia, chronic myelomonocytic leukemia (CMML) as well ashypereosinophilic syndrome, a rare proliferative hematological disorderand dermatofibrosarcoma protuberans, an infiltrative skin tumour.

The activity of the compounds of the invention as inhibitors of FGFR1-4,VEGFR and/or PDGFR A/B can be measured using the assays set forth in theexamples below and the level of activity exhibited by a given compoundcan be defined in terms of the IC₅₀ value. Preferred compounds of thepresent invention are compounds having an IC₅₀ value of less than 1 μM,more preferably less than 0.1 μM.

The invention provides compounds that have FGFR inhibiting or modulatingactivity, and which it is envisaged will be useful in preventing ortreating disease states or conditions mediated by FGFR kinases.

In one embodiment, there is provided a compound as defined herein foruse in therapy. In a further embodiment, there is provided a compound asdefined herein for use in the prophylaxis or treatment of a diseasestate or condition mediated by a FGFR kinase.

Thus, for example, it is envisaged that the compounds of the inventionwill be useful in alleviating or reducing the incidence of cancer.Therefore, in a further embodiment, there is provided a compound asdefined herein for use in the prophylaxis or treatment of cancer.

Accordingly, in one aspect, the invention provides the use of a compoundfor the manufacture of a medicament for the prophylaxis or treatment ofa disease state or condition mediated by a FGFR kinase, the compoundhaving the formula (I) as defined herein.

In one embodiment, there is provided the use of a compound as definedherein for the manufacture of a medicament for the prophylaxis ortreatment of a disease state or condition as described herein.

In a further embodiment, there is provided the use of a compound asdefined herein for the manufacture of a medicament for the prophylaxisor treatment of cancer.

Accordingly, the invention provides inter alia:

A method for the prophylaxis or treatment of a disease state orcondition mediated by a FGFR kinase, which method comprisesadministering to a subject in need thereof a compound of the formula (I)as defined herein.

In one embodiment, there is provided a method for the prophylaxis ortreatment of a disease state or condition as described herein, whichmethod comprises administering to a subject in need thereof a compoundof the formula (I) as defined herein.

In a further embodiment, there is provided a method for the prophylaxisor treatment of cancer, which method comprises administering to asubject in need thereof a compound of the formula (I) as defined herein.

A method for alleviating or reducing the incidence of a disease state orcondition mediated by a FGFR kinase, which method comprisesadministering to a subject in need thereof a compound of the formula (I)as defined herein.

A method of inhibiting a FGFR kinase, which method comprises contactingthe kinase with a kinase-inhibiting compound of the formula (I) asdefined herein.

A method of modulating a cellular process (for example cell division) byinhibiting the activity of a FGFR kinase using a compound of the formula(I) as defined herein.

A compound of formula (I) as defined herein for use as a modulator of acellular process (for example cell division) by inhibiting the activityof a FGFR kinase.

A compound of formula (I) as defined herein for use as a modulator (e.g.inhibitor) of FGFR.

The use of a compound of formula (I) as defined herein for themanufacture of a medicament for modulating (e.g. inhibiting) theactivity of FGFR.

Use of a compound of formula (I) as defined herein in the manufacture ofa medicament for modulating a cellular process (for example celldivision) by inhibiting the activity of a FGFR kinase.

The use of a compound of the formula (I) as defined herein for themanufacture of a medicament for prophylaxis or treatment of a disease orcondition characterised by up-regulation of a FGFR kinase (e.g. FGFR1 orFGFR2 or FGFR3 or FGFR4).

The use of a compound of the formula (I) as defined herein for themanufacture of a medicament for the prophylaxis or treatment of acancer, the cancer being one which is characterised by up-regulation ofa FGFR kinase (e.g. FGFR1 or FGFR2 or FGFR3 or FGFR4).

The use of a compound of the formula (I) as defined herein for themanufacture of a medicament for the prophylaxis or treatment of cancerin a patient selected from a sub-population possessing a geneticaberrations of FGFR3 kinase.

The use of a compound of the formula (I) as defined herein for themanufacture of a medicament for the prophylaxis or treatment of cancerin a patient who has been diagnosed as forming part of a sub-populationpossessing a genetic aberrations of FGFR3 kinase.

A method for the prophylaxis or treatment of a disease or conditioncharacterised by up-regulation of a FGFR kinase (e.g. FGFR1 or FGFR2 orFGFR3 or FGFR4), the method comprising administering a compound of theformula (I) as defined herein.

A method for alleviating or reducing the incidence of a disease orcondition characterised by up-regulation of a FGFR kinase (e.g. FGFR1 orFGFR2 or FGFR3 or FGFR4), the method comprising administering a compoundof the formula (I) as defined herein.

A method for the prophylaxis or treatment of (or alleviating or reducingthe incidence of) cancer in a patient suffering from or suspected ofsuffering from cancer; which method comprises (i) subjecting a patientto a diagnostic test to determine whether the patient possesses agenetic aberrations of FGFR3 gene; and (ii) where the patient doespossess the said variant, thereafter administering to the patient acompound of the formula (I) as defined herein having FGFR3 kinaseinhibiting activity.

A method for the prophylaxis or treatment of (or alleviating or reducingthe incidence of) a disease state or condition characterised byup-regulation of an FGFR kinase (e.g. e.g. FGFR1 or FGFR2 or FGFR3 orFGFR4); which method comprises (i) subjecting a patient to a diagnostictest to detect a marker characteristic of up-regulation of a FGFR kinase(e.g. FGFR1 or FGFR2 or FGFR3 or FGFR4) and (ii) where the diagnostictest is indicative of up-regulation of FGFR kinase, thereafteradministering to the patient a compound of the formula (I) as definedherein having FGFR kinase inhibiting activity.

In one embodiment, the disease mediated by FGFR kinases is a oncologyrelated disease (e.g. cancer). In one embodiment, the disease mediatedby FGFR kinases is a non-oncology related disease (e.g. any diseasedisclosed herein excluding cancer). In one embodiment the diseasemediated by FGFR kinases is a condition described herein. In oneembodiment the disease mediated by FGFR kinases is a skeletal conditiondescribed herein. Particular abnormalities in human skeletaldevelopment, include abnormal ossification of cranial sutures(craniosynostosis), Apert (AP) syndrome, Crouzon syndrome, Jackson-Weisssyndrome, Beare-Stevenson cutis gyrate syndrome, Pfeiffer syndrome,achondroplasia and thanatophoric dwarfism (also known as thanatophoricdysplasia).

Mutated Kinases

Drug resistant kinase mutations can arise in patient populations treatedwith kinase inhibitors. These occur, in part, in the regions of theprotein that bind to or interact with the particular inhibitor used intherapy. Such mutations reduce or increase the capacity of the inhibitorto bind to and inhibit the kinase in question. This can occur at any ofthe amino acid residues which interact with the inhibitor or areimportant for supporting the binding of said inhibitor to the target. Aninhibitor that binds to a target kinase without requiring theinteraction with the mutated amino acid residue will likely beunaffected by the mutation and will remain an effective inhibitor of theenzyme (Carter et al (2005), PNAS, 102(31), 11011-110116).

A study in gastric cancer patient samples showed the presence of twomutations in FGFR2, Ser167Pro in exon IIIa and a splice site mutation940-2A-G in exon IIIc. These mutations are identical to the germlineactivating mutations that cause craniosynotosis syndromes and wereobserved in 13% of primary gastric cancer tissues studied. In additionactivating mutations in FGFR3 were observed in 5% of the patient samplestested and overexpression of FGFRs has been correlated with a poorprognosis in this patient group (Jang et. al. (2001) Cancer Research 613541-3543.

There are mutations that have been observed in PDGFR in imatinib-treatedpatients, in particular the T674I mutation. The clinical importance ofthese mutations may grow considerably, as to date it appears torepresent the primary mechanism of resistance to src/Abl inhibitors inpatients.

In addition there are chromosomal translocations or point mutations thathave been observed in FGFR which give rise to gain-of-function,over-expressed, or constitutively active biological states.

The compounds of the invention would therefore find particularapplication in relation to cancers which express a mutated moleculartarget such as FGFR or PDGFR including PDGFR-beta and PDGFR-alpha inparticular the T674I mutation of PDGFR. Diagnosis of tumours with suchmutations could be performed using techniques known to a person skilledin the art and as described herein such as RTPCR and FISH.

It has been suggested that mutations of a conserved threonine residue atthe ATP binding site of FGFR would result in inhibitor resistance. Theamino acid valine 561 has been mutated to a methionine in FGFR1 whichcorresponds to previously reported mutations found in Abl (T315) andEGFR (T766) that have been shown to confer resistance to selectiveinhibitors. Assay data for FGFR1 V561M showed that this mutationconferred resistance to a tyrosine kinase inhibitor compared to that ofthe wild type.

Advantages of the Compositions of the Invention

The compounds of the formula (I) have a number of advantages over priorart compounds.

For example, the compounds of formula (I) have advantageous ADMET andphysiochemical properties over prior art compounds.

Pharmaceutical Formulations

While it is possible for the active compound to be administered alone,it is preferable to present it as a pharmaceutical composition (e.g.formulation) comprising at least one active compound of the inventiontogether with one or more pharmaceutically acceptable carriers,adjuvants, excipients, diluents, fillers, buffers, stabilisers,preservatives, lubricants, or other materials well known to thoseskilled in the art and optionally other therapeutic or prophylacticagents.

Thus, the present invention further provides pharmaceuticalcompositions, as defined above, and methods of making a pharmaceuticalcomposition comprising admixing at least one active compound, as definedabove, together with one or more pharmaceutically acceptable carriers,excipients, buffers, adjuvants, stabilizers, or other materials, asdescribed herein.

The term “pharmaceutically acceptable” as used herein pertains tocompounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of a subject (e.g. human) without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio. Each carrier,excipient, etc. must also be “acceptable” in the sense of beingcompatible with the other ingredients of the formulation.

Pharmaceutical compositions containing compounds of the formula (I) canbe formulated in accordance with known techniques, see for example,Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton,Pa., USA.

Accordingly, in a further aspect, the invention provides compounds ofthe formula (I) and sub-groups thereof as defined herein in the form ofpharmaceutical compositions.

The pharmaceutical compositions can be in any form suitable for oral,parenteral, topical, intranasal, ophthalmic, otic, rectal,intra-vaginal, or transdermal administration. Where the compositions areintended for parenteral administration, they can be formulated forintravenous, intramuscular, intraperitoneal, subcutaneous administrationor for direct delivery into a target organ or tissue by injection,infusion or other means of delivery. The delivery can be by bolusinjection, short term infusion or longer term infusion and can be viapassive delivery or through the utilisation of a suitable infusion pump.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions which maycontain anti-oxidants, buffers, bacteriostats, co-solvents, organicsolvent mixtures, cyclodextrin complexation agents, emulsifying agents(for forming and stabilizing emulsion formulations), liposome componentsfor forming liposomes, gellable polymers for forming polymeric gels,lyophilisation protectants and combinations of agents for, inter alia,stabilising the active ingredient in a soluble form and rendering theformulation isotonic with the blood of the intended recipient.Pharmaceutical formulations for parenteral administration may also takethe form of aqueous and non-aqueous sterile suspensions which mayinclude suspending agents and thickening agents (Strickly, R. G. (2004)Solubilizing Excipients in oral and injectable formulations,Pharmaceutical Research, Vol 21(2)p 201-230).

Liposomes are closed spherical vesicles composed of outer lipid bilayermembranes and an inner aqueous core and with an overall diameter of <100μm. Depending on the level of hydrophobicity, moderately hydrophobicdrugs can be solubilized by liposomes if the drug becomes encapsulatedor intercalated within the liposome. Hydrophobic drugs can also besolubilized by liposomes if the drug molecule becomes an integral partof the lipid bilayer membrane, and in this case, the hydrophobic drug isdissolved in the lipid portion of the lipid bilayer.

The formulations may be presented in unit-dose or multi-dose containers,for example sealed ampoules and vials, and may be stored in afreeze-dried (lyophilised) condition requiring only the addition of thesterile liquid carrier, for example water for injections, immediatelyprior to use.

The pharmaceutical formulation can be prepared by lyophilising acompound of formula (I), or sub-groups thereof. Lyophilisation refers tothe procedure of freeze-drying a composition. Freeze-drying andlyophilisation are therefore used herein as synonyms.

Extemporaneous injection solutions and suspensions may be prepared fromsterile powders, granules and tablets.

Pharmaceutical compositions of the present invention for parenteralinjection can also comprise pharmaceutically acceptable sterile aqueousor non-aqueous solutions, dispersions, suspensions or emulsions as wellas sterile powders for reconstitution into sterile injectable solutionsor dispersions just prior to use. Examples of suitable aqueous andnonaqueous carriers, diluents, solvents or vehicles include water,ethanol, polyols (such as glycerol, propylene glycol, polyethyleneglycol, and the like), carboxymethylcellulose and suitable mixturesthereof, vegetable oils (such as olive oil), and injectable organicesters such as ethyl oleate. Proper fluidity can be maintained, forexample, by the use of coating materials such as lecithin, by themaintenance of the required particle size in the case of dispersions,and by the use of surfactants.

The compositions of the present invention may also contain adjuvantssuch as preservatives, wetting agents, emulsifying agents, anddispersing agents. Prevention of the action of microorganisms may beensured by the inclusion of various antibacterial and antifungal agents,for example, paraben, chlorobutanol, phenol sorbic acid, and the like.It may also be desirable to include isotonic agents such as sugars,sodium chloride, and the like. Prolonged absorption of the injectablepharmaceutical form may be brought about by the inclusion of agentswhich delay absorption such as aluminium monostearate and gelatin.

In one preferred embodiment of the invention, the pharmaceuticalcomposition is in a form suitable for i.v. administration, for exampleby injection or infusion. For intravenous administration, the solutioncan be dosed as is, or can be injected into an infusion bag (containinga pharmaceutically acceptable excipient, such as 0.9% saline or 5%dextrose), before administration.

In another preferred embodiment, the pharmaceutical composition is in aform suitable for sub-cutaneous (s.c.) administration.

Pharmaceutical dosage forms suitable for oral administration includetablets, capsules, caplets, pills, lozenges, syrups, solutions, powders,granules, elixirs and suspensions, sublingual tablets, wafers or patchesand buccal patches.

Thus, tablet compositions can contain a unit dosage of active compoundtogether with an inert diluent or carrier such as a sugar or sugaralcohol, eg; lactose, sucrose, sorbitol or mannitol; and/or a non-sugarderived diluent such as sodium carbonate, calcium phosphate, calciumcarbonate, or a cellulose or derivative thereof such as methylcellulose, ethyl cellulose, hydroxypropyl methyl cellulose, and starchessuch as corn starch. Tablets may also contain such standard ingredientsas binding and granulating agents such as polyvinylpyrrolidone,disintegrants (e.g. swellable crosslinked polymers such as crosslinkedcarboxymethylcellulose), lubricating agents (e.g. stearates),preservatives (e.g. parabens), antioxidants (e.g. BHT), buffering agents(for example phosphate or citrate buffers), and effervescent agents suchas citrate/bicarbonate mixtures. Such excipients are well known and donot need to be discussed in detail here.

Capsule formulations may be of the hard gelatin or soft gelatin varietyand can contain the active component in solid, semi-solid, or liquidform. Gelatin capsules can be formed from animal gelatin or synthetic orplant derived equivalents thereof.

The solid dosage forms (eg; tablets, capsules etc.) can be coated orun-coated, but typically have a coating, for example a protective filmcoating (e.g. a wax or varnish) or a release controlling coating. Thecoating (e.g. a Eudragit™ type polymer) can be designed to release theactive component at a desired location within the gastrointestinaltract. Thus, the coating can be selected so as to degrade under certainpH conditions within the gastrointestinal tract, thereby selectivelyrelease the compound in the stomach or in the ileum or duodenum.

Instead of, or in addition to, a coating, the drug can be presented in asolid matrix comprising a release controlling agent, for example arelease delaying agent which may be adapted to selectively release thecompound under conditions of varying acidity or alkalinity in thegastrointestinal tract. Alternatively, the matrix material or releaseretarding coating can take the form of an erodible polymer (e.g. amaleic anhydride polymer) which is substantially continuously eroded asthe dosage form passes through the gastrointestinal tract. As a furtheralternative, the active compound can be formulated in a delivery systemthat provides osmotic control of the release of the compound. Osmoticrelease and other delayed release or sustained release formulations maybe prepared in accordance with methods well known to those skilled inthe art.

The pharmaceutical compositions comprise from approximately 1% toapproximately 95%, preferably from approximately 20% to approximately90%, active ingredient. Pharmaceutical compositions according to theinvention may be, for example, in unit dose form, such as in the form ofampoules, vials, suppositories, dragées, tablets or capsules.

Pharmaceutical compositions for oral administration can be obtained bycombining the active ingredient with solid carriers, if desiredgranulating a resulting mixture, and processing the mixture, if desiredor necessary, after the addition of appropriate excipients, intotablets, dragee cores or capsules. It is also possible for them to beincorporated into plastics carriers that allow the active ingredients todiffuse or be released in measured amounts.

The compounds of the invention can also be formulated as soliddispersions. Solid dispersions are homogeneous extremely fine dispersephases of two or more solids.

Solid solutions (molecularly disperse systems), one type of soliddispersion, are well known for use in pharmaceutical technology (see(Chiou and Riegelman (1971), J. Pharm. Sci., 60, 1281-1300) and areuseful in increasing dissolution rates and increasing thebioavailability of poorly water-soluble drugs.

This invention also provides solid dosage forms comprising the solidsolution described above. Solid dosage forms include tablets, capsulesand chewable tablets. Known excipients can be blended with the solidsolution to provide the desired dosage form. For example, a capsule cancontain the solid solution blended with (a) a disintegrant and alubricant, or (b) a disintegrant, a lubricant and a surfactant. A tabletcan contain the solid solution blended with at least one disintegrant, alubricant, a surfactant, and a glidant. The chewable tablet can containthe solid solution blended with a bulking agent, a lubricant, and ifdesired an additional sweetening agent (such as an artificialsweetener), and suitable flavours.

The pharmaceutical formulations may be presented to a patient in“patient packs” containing an entire course of treatment in a singlepackage, usually a blister pack. Patient packs have an advantage overtraditional prescriptions, where a pharmacist divides a patient's supplyof a pharmaceutical from a bulk supply, in that the patient always hasaccess to the package insert contained in the patient pack, normallymissing in patient prescriptions. The inclusion of a package insert hasbeen shown to improve patient compliance with the physician'sinstructions.

Compositions for topical use include ointments, creams, sprays, patches,gels, liquid drops and inserts (for example intraocular inserts). Suchcompositions can be formulated in accordance with known methods.

Examples of formulations for rectal or intra-vaginal administrationinclude pessaries and suppositories which may be, for example, formedfrom a shaped moldable or waxy material containing the active compound.

Compositions for administration by inhalation may take the form ofinhalable powder compositions or liquid or powder sprays, and can beadministrated in standard form using powder inhaler devices or aerosoldispensing devices. Such devices are well known. For administration byinhalation, the powdered formulations typically comprise the activecompound together with an inert solid powdered diluent such as lactose.

The compounds of the formula (I) will generally be presented in unitdosage form and, as such, will typically contain sufficient compound toprovide a desired level of biological activity. For example, aformulation may contain from 1 nanogram to 2 grams of active ingredient,e.g. from 1 nanogram to 2 milligrams of active ingredient. Within thisrange, particular sub-ranges of compound are 0.1 milligrams to 2 gramsof active ingredient (more usually from 10 milligrams to 1 gram, e.g. 50milligrams to 500 milligrams), or 1 microgram to 20 milligrams (forexample 1 microgram to 10 milligrams, e.g. 0.1 milligrams to 2milligrams of active ingredient).

For oral compositions, a unit dosage form may contain from 1 milligramto 2 grams, more typically 10 milligrams to 1 gram, for example 50milligrams to 1 gram, e.g. 100 milligrams to 1 gram, of active compound.

The active compound will be administered to a patient in need thereof(for example a human or animal patient) in an amount sufficient toachieve the desired therapeutic effect.

The skilled person will have the expertise to select the appropriateamounts of ingredients for use in the formulations. For example tabletsand capsules typically contain 0-20% disintegrants, 0-5% lubricants,0-5% flow aids and/or 0-100% fillers/ or bulking agents (depending ondrug dose). They may also contain 0-10% polymer binders, 0-5%antioxidants, 0-5% Pigments. Slow release tablets would in additioncontain 0-100% polymers (depending on dose). The film coats of thetablet or capsule typically contain 0-10% polymers, 0-3% pigments,and/or 0-2% plasticizers.

Parenteral formulations typically contain 0-20% buffers, 0-50%cosolvents, and/or 0-100% Water for Injection (WFI) (depending on doseand if freeze dried). Formulations for intramuscular depots may alsocontain 0-100% oils.

EXAMPLES OF PHARMACEUTICAL FORMULATIONS

(i) Tablet Formulation

A tablet composition containing a compound of the formula (I) isprepared by mixing 50 mg of the compound with 197 mg of lactose (BP) asdiluent, and 3 mg magnesium stearate as a lubricant and compressing toform a tablet in known manner.

(ii) Capsule Formulation

A capsule formulation is prepared by mixing 100 mg of a compound of theformula (I) with 100 mg lactose and filling the resulting mixture intostandard opaque hard gelatin capsules.

(iii) Injectable Formulation I

A parenteral composition for administration by injection can be preparedby dissolving a compound of the formula (I) (e.g. in a salt form) inwater containing 10% propylene glycol to give a concentration of activecompound of 1.5% by weight. The solution is then sterilised byfiltration, filled into an ampoule and sealed.

(iv) Injectable Formulation II

A parenteral composition for injection is prepared by dissolving inwater a compound of the formula (I) (e.g. in salt form) (2 mg/ml) andmannitol (50 mg/ml), sterile filtering the solution and filling intosealable 1 ml vials or ampoules.

(v) Injectable formulation III

A formulation for i.v. delivery by injection or infusion can be preparedby dissolving the compound of formula (I) (e.g. in a salt form) in waterat 20 mg/ml. The vial is then sealed and sterilised by autoclaving.

(vi) Injectable formulation IV

A formulation for i.v. delivery by injection or infusion can be preparedby dissolving the compound of formula (I) (e.g. in a salt form) in watercontaining a buffer (e.g. 0.2 M acetate pH 4.6) at 20 mg/ml. The vial isthen sealed and sterilised by autoclaving.

(vii) Subcutaneous Injection Formulation

A composition for sub-cutaneous administration is prepared by mixing acompound of the formula (I) with pharmaceutical grade corn oil to give aconcentration of 5 mg/ml. The composition is sterilised and filled intoa suitable container.

(viii) Lyophilised formulation

Aliquots of formulated compound of formula (I) are put into 50 ml vialsand lyophilized. During lyophilisation, the compositions are frozenusing a one-step freezing protocol at (−45° C.). The temperature israised to −10° C. for annealing, then lowered to freezing at −45° C.,followed by primary drying at +25° C. for approximately 3400 minutes,followed by a secondary drying with increased steps if temperature to50° C. The pressure during primary and secondary drying is set at 80millitorr.

Methods of Treatment

It is envisaged that the compounds of the formula (I) and sub-groupsthereof as defined herein will be useful in the prophylaxis or treatmentof a range of disease states or conditions mediated by FGFR. Examples ofsuch disease states and conditions are set out above.

The compounds are generally administered to a subject in need of suchadministration, for example a human or animal patient, preferably ahuman. The compounds will typically be administered in amounts that aretherapeutically or prophylactically useful and which generally arenon-toxic.

However, in certain situations (for example in the case of lifethreatening diseases), the benefits of administering a compound of theformula (I) may outweigh the disadvantages of any toxic effects or sideeffects, in which case it may be considered desirable to administercompounds in amounts that are associated with a degree of toxicity.

The compounds may be administered over a prolonged term to maintainbeneficial therapeutic effects or may be administered for a short periodonly. Alternatively they may be administered in a pulsatile orcontinuous manner.

A typical daily dose of the compound of formula (I) can be in the rangefrom 100 picograms to 100 milligrams per kilogram of body weight, moretypically 5 nanograms to 25 milligrams per kilogram of bodyweight, andmore usually 10 nanograms to 15 milligrams per kilogram (e.g. 10nanograms to 10 milligrams, and more typically 1 microgram per kilogramto 20 milligrams per kilogram, for example 1 microgram to 10 milligramsper kilogram) per kilogram of bodyweight although higher or lower dosesmay be administered where required. The compound of the formula (I) canbe administered on a daily basis or on a repeat basis every 2, or 3, or4, or 5, or 6, or 7, or 10 or 14, or 21, or 28 days for example.

The compounds of the invention may be administered orally in a range ofdoses, for example 1 to 1500 mg, 2 to 800 mg, or 5 to 500 mg, e.g. 2 to200 mg or 10 to 1000 mg, particular examples of doses including 10, 20,50 and 80 mg. The compound may be administered once or more than onceeach day. The compound can be administered continuously (i.e. takenevery day without a break for the duration of the treatment regimen).Alternatively, the compound can be administered intermittently, i.e.taken continuously for a given period such as a week, then discontinuedfor a period such as a week and then taken continuously for anotherperiod such as a week and so on throughout the duration of the treatmentregimen. Examples of treatment regimens involving intermittentadministration include regimens wherein administration is in cycles ofone week on, one week off; or two weeks on, one week off; or three weekson, one week off; or two weeks on, two weeks off; or four weeks on twoweeks off; or one week on three weeks off—for one or more cycles, e.g.2, 3, 4, 5, 6, 7, 8, 9 or 10 or more cycles.

In one particular dosing schedule, a patient will be given an infusionof a compound of the formula (I) for periods of one hour daily for up toten days in particular up to five days for one week, and the treatmentrepeated at a desired interval such as two to four weeks, in particularevery three weeks.

More particularly, a patient may be given an infusion of a compound ofthe formula (I) for periods of one hour daily for 5 days and thetreatment repeated every three weeks.

In another particular dosing schedule, a patient is given an infusionover 30 minutes to 1 hour followed by maintenance infusions of variableduration, for example 1 to 5 hours, e.g. 3 hours.

In a further particular dosing schedule, a patient is given a continuousinfusion for a period of 12 hours to 5 days, an in particular acontinuous infusion of 24 hours to 72 hours.

Ultimately, however, the quantity of compound administered and the typeof composition used will be commensurate with the nature of the diseaseor physiological condition being treated and will be at the discretionof the physician.

The compounds as defined herein can be administered as the soletherapeutic agent or they can be administered in combination therapywith one of more other compounds for treatment of a particular diseasestate, for example a neoplastic disease such as a cancer as hereinbeforedefined. Examples of other therapeutic agents or treatments that may beadministered together (whether concurrently or at different timeintervals) with the compounds of the formula (I) include but are notlimited to:

-   Topoisomerase I inhibitors-   Antimetabolites-   Tubulin targeting agents-   DNA binder and topoisomerase II inhibitors-   Alkylating Agents-   Monoclonal Antibodies.-   Anti-Hormones-   Signal Transduction Inhibitors-   Proteasome Inhibitors-   DNA methyl transferases-   Cytokines and retinoids-   Chromatin targeted therapies-   Radiotherapy, and,

Other therapeutic or prophylactic agents; for example agents that reduceor alleviate some of the side effects associated with chemotherapy.Particular examples of such agents include anti-emetic agents and agentsthat prevent or decrease the duration of chemotherapy-associatedneutropenia and prevent complications that arise from reduced levels ofred blood cells or white blood cells, for example erythropoietin (EPO),granulocyte macrophage-colony stimulating factor (GM-CSF), andgranulocyte-colony stimulating factor (G-CSF). Also included are agentsthat inhibit bone resorption such as bisphosphonate agents e.g.zoledronate, pamidronate and ibandronate, agents that suppressinflammatory responses (such as dexamethazone, prednisone, andprednisolone) and agents used to reduce blood levels of growth hormoneand IGF-I in acromegaly patients such as synthetic forms of the brainhormone somatostatin, which includes octreotide acetate which is along-acting octapeptide with pharmacologic properties mimicking those ofthe natural hormone somatostatin. Further included are agents such asleucovorin, which is used as an antidote to drugs that decrease levelsof folic acid, or folinic acid it self and agents such as megestrolacetate which can be used for the treatment of side-effects includingoedema and thromoembolic episodes.

Each of the compounds present in the combinations of the invention maybe given in individually varying dose schedules and via differentroutes.

Where the compound of the formula (I) is administered in combinationtherapy with one, two, three, four or more other therapeutic agents(preferably one or two, more preferably one), the compounds can beadministered simultaneously or sequentially. When administeredsequentially, they can be administered at closely spaced intervals (forexample over a period of 5-10 minutes) or at longer intervals (forexample 1, 2, 3, 4 or more hours apart, or even longer periods apartwhere required), the precise dosage regimen being commensurate with theproperties of the therapeutic agent(s).

The compounds of the invention may also be administered in conjunctionwith non-chemotherapeutic treatments such as radiotherapy, photodynamictherapy, gene therapy; surgery and controlled diets.

For use in combination therapy with another chemotherapeutic agent, thecompound of the formula (I) and one, two, three, four or more othertherapeutic agents can be, for example, formulated together in a dosageform containing two, three, four or more therapeutic agents. In analternative, the individual therapeutic agents may be formulatedseparately and presented together in the form of a kit, optionally withinstructions for their use.

A person skilled in the art would know through his or her common generalknowledge the dosing regimes and combination therapies to use.

Methods of Diagnosis

Prior to administration of a compound of the formula (I), a patient maybe screened to determine whether a disease or condition from which thepatient is or may be suffering is one which would be susceptible totreatment with a compound having activity against FGFR, VEGFR and/orPDGFR.

For example, a biological sample taken from a patient may be analysed todetermine whether a condition or disease, such as cancer, that thepatient is or may be suffering from is one which is characterised by agenetic abnormality or abnormal protein expression which leads toup-regulation of the levels or activity of FGFR, VEGFR and/or PDGFR orto sensitisation of a pathway to normal FGFR, VEGFR and/or PDGFRactivity, or to upregulation of these growth factor signalling pathwayssuch as growth factor ligand levels or growth factor ligand activity orto upregulation of a biochemical pathway downstream of FGFR, VEGFRand/or PDGFR activation.

Examples of such abnormalities that result in activation orsensitisation of the FGFR, VEGFR and/or PDGFR signal include loss of, orinhibition of apoptotic pathways, up-regulation of the receptors orligands, or presence of mutant variants of the receptors or ligands e.gPTK variants. Tumours with mutants of FGFR1, FGFR2 or FGFR3 or FGFR4 orup-regulation, in particular over-expression of FGFR1, orgain-of-function mutants of FGFR2 or FGFR3 may be particularly sensitiveto FGFR inhibitors.

For example, point mutations engendering gain-of-function in FGFR2 havebeen identified in a number of conditions (Lemonnier, et al. (2001), J.Bone Miner. Res., 16, 832-845). In particular activating mutations inFGFR2 have been identified in 10% of endometrial tumours (Pollock et al,Oncogene, 2007, 26, 7158-7162).

In addition, genetic aberrations of the FGFR3 receptor tyrosine kinasesuch as chromosomal translocations or point mutations resulting inectopically expressed or deregulated, constitutively active, FGFR3receptors have been identified and are linked to a subset of multiplemyelomas, bladder and cervical carcinomas (Powers, C. J., et al. (2000),Endocr. Rel. Cancer, 7, 165). A particular mutation T674I of the PDGFreceptor has been identified in imatinib-treated patients.

In addition, a gene amplification of 8p12-p11.2 was demonstrated in ˜50%of lobular breast cancer (CLC) cases and this was shown to be linkedwith an increased expression of FGFR1. Preliminary studies with siRNAdirected against FGFR1, or a small molecule inhibitor of the receptor,showed cell lines harbouring this amplification to be particularlysensitive to inhibition of this signalling pathway (Reis-Filho et al.(2006) Clin Cancer Res. 12(22): 6652-6662).

Alternatively, a biological sample taken from a patient may be analysedfor loss of a negative regulator or suppressor of FGFR, VEGFR or PDGFR.In the present context, the term “loss” embraces the deletion of a geneencoding the regulator or suppressor, the truncation of the gene (forexample by mutation), the truncation of the transcribed product of thegene, or the inactivation of the transcribed product (e.g. by pointmutation) or sequestration by another gene product.

The term up-regulation includes elevated expression or over-expression,including gene amplification (i.e. multiple gene copies) and increasedexpression by a transcriptional effect, and hyperactivity andactivation, including activation by mutations. Thus, the patient may besubjected to a diagnostic test to detect a marker characteristic ofup-regulation of FGFR, VEGFR and/or PDGFR. The term diagnosis includesscreening. By marker we include genetic markers including, for example,the measurement of DNA composition to identify mutations of FGFR, VEGFRand/or PDGFR. The term marker also includes markers which arecharacteristic of up regulation of FGFR, VEGFR and/or PDGFR, includingenzyme activity, enzyme levels, enzyme state (e.g. phosphorylated ornot) and mRNA levels of the aforementioned proteins.

The diagnostic tests and screens are typically conducted on a biologicalsample selected from tumour biopsy samples, blood samples (isolation andenrichment of shed tumour cells), stool biopsies, sputum, chromosomeanalysis, pleural fluid, peritoneal fluid, buccal spears, biopsy orurine.

Methods of identification and analysis of mutations and up-regulation ofproteins are known to a person skilled in the art. Screening methodscould include, but are not limited to, standard methods such asreverse-transcriptase polymerase chain reaction (RT-PCR) or in-situhybridization such as fluorescence in situ hybridization (FISH).

Identification of an individual carrying a mutation in FGFR, VEGFRand/or PDGFR may mean that the patient would be particularly suitablefor treatment with a FGFR, VEGFR and/or PDGFR inhibitor. Tumours maypreferentially be screened for presence of a FGFR, VEGFR and/or PDGFRvariant prior to treatment. The screening process will typically involvedirect sequencing, oligonucleotide microarray analysis, or a mutantspecific antibody. In addition, diagnosis of tumours with such mutationscould be performed using techniques known to a person skilled in the artand as described herein such as RT-PCR and FISH.

In addition, mutant forms of, for example FGFR or VEGFR2, can beidentified by direct sequencing of, for example, tumour biopsies usingPCR and methods to sequence PCR products directly as hereinbeforedescribed. The skilled artisan will recognize that all such well-knowntechniques for detection of the over expression, activation or mutationsof the aforementioned proteins could be applicable in the present case.

In screening by RT-PCR, the level of mRNA in the tumour is assessed bycreating a cDNA copy of the mRNA followed by amplification of the cDNAby PCR. Methods of PCR amplification, the selection of primers, andconditions for amplification, are known to a person skilled in the art.Nucleic acid manipulations and PCR are carried out by standard methods,as described for example in Ausubel, F. M. et al., eds. CurrentProtocols in Molecular Biology, 2004, John Wiley & Sons Inc., or Innis,M. A. et al., eds. PCR Protocols: a guide to methods and applications,1990, Academic Press, San Diego. Reactions and manipulations involvingnucleic acid techniques are also described in Sambrook et al., 2001,3^(rd) Ed, Molecular Cloning: A Laboratory Manual, Cold Spring HarborLaboratory Press. Alternatively a commercially available kit for RT-PCR(for example Roche Molecular Biochemicals) may be used, or methodologyas set forth in U.S. Pat. Nos. 4,666,828; 4,683,202; 4,801,531;5,192,659, 5,272,057, 5,882,864, and 6,218,529 and incorporated hereinby reference.

An example of an in-situ hybridisation technique for assessing mRNAexpression would be fluorescence in-situ hybridisation (FISH) (seeAngerer (1987), Meth. Enzymol., 152, 649).

Generally, in situ hybridization comprises the following major steps:(1) fixation of tissue to be analyzed; (2) prehybridization treatment ofthe sample to increase accessibility of target nucleic acid, and toreduce nonspecific binding; (3) hybridization of the mixture of nucleicacids to the nucleic acid in the biological structure or tissue; (4)post-hybridization washes to remove nucleic acid fragments not bound inthe hybridization, and (5) detection of the hybridized nucleic acidfragments. The probes used in such applications are typically labelled,for example, with radioisotopes or fluorescent reporters. Preferredprobes are sufficiently long, for example, from about 50, 100, or 200nucleotides to about 1000 or more nucleotides, to enable specifichybridization with the target nucleic acid(s) under stringentconditions. Standard methods for carrying out FISH are described inAusubel, F. M. et al., eds. Current Protocols in Molecular Biology,2004, John Wiley & Sons Inc and Fluorescence In Situ Hybridization:Technical Overview by John M. S. Bartlett in Molecular Diagnosis ofCancer, Methods and Protocols, 2nd ed.; ISBN: 1-59259-760-2; March 2004,pps. 077-088; Series: Methods in Molecular Medicine.

Methods for gene expression profiling are described by (DePrimo et al.(2003), BMC Cancer, 3:3). Briefly, the protocol is as follows:double-stranded cDNA is synthesized from total RNA Using a (dT)24oligomer for priming first-strand cDNA synthesis, followed by secondstrand cDNA synthesis with random hexamer primers. The double-strandedcDNA is used as a template for in vitro transcription of cRNA usingbiotinylated ribonucleotides. cRNA is chemically fragmented according toprotocols described by Affymetrix (Santa Clara, Calif., USA), and thenhybridized overnight on Human Genome Arrays.

Alternatively, the protein products expressed from the mRNAs may beassayed by immunohistochemistry of tumour samples, solid phaseimmunoassay with microtitre plates, Western blotting, 2-dimensionalSDS-polyacrylamide gel electrophoresis, ELISA, flow cytometry and othermethods known in the art for detection of specific proteins. Detectionmethods would include the use of site specific antibodies. The skilledperson will recognize that all such well-known techniques for detectionof upregulation of FGFR, VEGFR and/or PDGFR, or detection of FGFR, VEGFRand/or PDGFR variants or mutants could be applicable in the presentcase.

Abnormal levels of proteins such as FGFR or VEGFR can be measured usingstandard enzyme assays, for example, those assays described herein.Activation or overexpression could also be detected in a tissue sample,for example, a tumour tissue. By measuring the tyrosine kinase activitywith an assay such as that from Chemicon International. The tyrosinekinase of interest would be immunoprecipitated from the sample lysateand its activity measured.

Alternative methods for the measurement of the over expression oractivation of FGFR or VEGFR including the isoforms thereof, include themeasurement of microvessel density. This can for example be measuredusing methods described by Orre and Rogers (Int J Cancer (1999), 84(2),101-8). Assay methods also include the use of markers, for example, inthe case of VEGFR these include CD31, CD34 and CD105 (Mineo et al.(2004) J Clin Pathol. 57(6), 591-7).

Therefore all of these techniques could also be used to identify tumoursparticularly suitable for treatment with the compounds of the invention.

The compounds of the invention are particular useful in treatment of apatient having a mutated FGFR. The G697C mutation in FGFR3 is observedin 62% of oral squamous cell carcinomas and causes constitutiveactivation of the kinase activity. Activating mutations of FGFR3 havealso been identified in bladder carcinoma cases. These mutations were of6 kinds with varying degrees of prevalence: R248C, S249C, G372C, S373C,Y375C, K652Q. In addition, a Gly388Arg polymorphism in FGFR4 has beenfound to be associated with increased incidence and aggressiveness ofprostate, colon, lung and breast cancer.

Therefore in a further aspect of the invention includes use of acompound according to the invention for the manufacture of a medicamentfor the treatment or prophylaxis of a disease state or condition in apatient who has been screened and has been determined as suffering from,or being at risk of suffering from, a disease or condition which wouldbe susceptible to treatment with a compound having activity againstFGFR.

Particular mutations a patient is screened for include G697C, R248C,S249C, G372C, S373C, Y375C, K652Q mutations in FGFR3 and Gly388Argpolymorphism in FGFR4.

In another aspect of the inventions includes a compound of the inventionfor use in the prophylaxis or treatment of cancer in a patient selectedfrom a sub-population possessing a variant of the FGFR gene (for exampleG697C mutation in FGFR3 and Gly388Arg polymorphism in FGFR4).

MRI determination of vessel normalization (e.g. using MRI gradient echo,spin echo, and contrast enhancement to measure blood volume, relativevessel size, and vascular permeability) in combination with circulatingbiomarkers (circulating progenitor cells (CPCs), CECs, SDF1, and FGF2)may also be used to identify VEGFR2-resistant tumours for treatment witha compound of the invention.

General Synthetic Routes

Analytical LC-MS System and Method Description

In the examples, the compounds prepared were characterised by liquidchromatography and mass spectroscopy using commercially availablesystems (Waters Platform LC-MS system, Waters Fractionlynx LC-MSsystem), standard operating conditions and commercially availablecolumns (Phenomenex, Waters etc) but a person skilled in the art willappreciate that alternative systems and methods could be used. Whereatoms with different isotopes are present and a single mass quoted, themass quoted for the compound is the monoisotopic mass (i.e. ³⁵Cl; ⁷⁹Bretc.).

Mass Directed Purification LC-MS System

Preparative LC-MS (or HPLC) is a standard and effective method used forthe purification of small organic molecules such as the compoundsdescribed herein. The methods for the liquid chromatography (LC) andmass spectrometry (MS) can be varied to provide better separation of thecrude materials and improved detection of the samples by MS.Optimisation of the preparative gradient LC method will involve varyingcolumns, volatile eluents and modifiers, and gradients. Methods are wellknown in the art for optimising preparative LC-MS methods and then usingthem to purify compounds. Such methods are described in Rosentreter U,Huber U.; Optimal fraction collecting in preparative LC/MS; J CombChem.; 2004; 6(2), 159-64 and Leister W, Strauss K, Wisnoski D, Zhao Z,Lindsley C., Development of a custom high-throughput preparative liquidchromatography/mass spectrometer platform for the preparativepurification and analytical analysis of compound libraries; J CombChem.; 2003; 5(3); 322-9.

Two such systems for purifying compounds via preparative LC-MS are theWaters Fractionlynx system or the Agilent 1100 LC-MS preparative systemalthough a person skilled in the art will appreciate that alternativesystems and methods could be used. In particular, reverse phase methodswere used for preparative HPLC for the compounds described herein, butnormal phase preparative LC based methods might be used in place of thereverse phase methods. Most preparative LC-MS systems utilise reversephase LC and volatile acidic modifiers, since the approach is veryeffective for the purification of small molecules and because theeluents are compatible with positive ion electrospray mass spectrometry.According to the analytical trace obtained the most appropriatepreparative chromatography type is chosen. A typical routine is to runan analytical LC-MS using the type of chromatography (low or high pH)most suited for compound structure. Once the analytical trace showedgood chromatography a suitable preparative method of the same type ischosen. A range of chromatographic solutions e.g. normal or reversephase LC; acidic, basic, polar, or lipophilic buffered mobile phase;basic modifiers could be used to purify the compounds. From theinformation provided someone skilled in the art could purify thecompounds described herein by preparative LC-MS.

All compounds were usually dissolved in 100% MeOH or 100% DMSO.

General Route A

Procedure A1—Imidazopyridine Ring Formation

To a solution of Methyl 2-aminopyridine-4-carboxylate (10.0 g, 66 mmol,1.0 equiv) in EtOH (150 ml) was added NaHCO₃ (11.1 g, 132 mmol, 2.0equiv) followed by chloroacetaldehyde (50% by weight in water, 13.0 ml,99 mmol, 1.5 equiv). The mixture was refluxed for 2 h. Solvents wereremoved under reduced pressure and the crude mixture was partitionedbetween water and EtOAc. The resulting precipitate was washed with Et₂Oand recrystallised from MeOH/Et₂O to afford 8.4 g of product. ¹H NMR(400 MHz, DMSO-d6): 8.66 (1H, d), 8.16 (2H, s), 7.80 (1H, s), 7.33 (1H,d), 3.90 (3H, s). MS: [M+H]⁺177.

Procedure A2—Ester Hydrolysis

To a solution of methyl imidazo[1,2-a]pyridine-7-carboxylate (3.0 g,17.04 mmol, 1.0 equiv) in EtOH (150 ml) was added 2M aqueous KOH (85 ml,170 mmol, 10 equiv). The solution was heated for 30 min at 60° C. Aftercooling to room temperature, the reaction was neutralized (HCl) andsolvents were removed under reduced pressure. The residue was stirred inEtOH (2×100 ml) and filtered. The solvent was removed under reducedpressure and the resulting product was used in the next step withoutfurther purification. MS: [M+H]⁺163.

Procedure A3—General Amide Bond Formation

To a solution of imidazo[1,2-a]pyridine-7-carboxylic acid (1.0 equiv) inDMF/H₂O (50:1) was added TBTU (1.5 equiv) and HOBT (1.5 equiv). Thereaction was stirred at room temperature for 30 min before the amine(2.0 equiv) was added. The resulting solution was stirred at roomtemperature for 16 h. The reaction mixture was poured onto an SCXcartridge and washed with MeOH (2 column volumes) before the product waseluted with methanolic ammonia (2 column volumes). The solvent wasremoved under reduced pressure and, where necessary the product waspurified by chromatography on silica (0→50% MeOH/Et₂O).

Amine Product MS: [M + H]⁺ Methyl amineImidazo[1,2-a]pyridine-7-carboxylic 176 acid methylamide Dimethyl amineImidazo[1,2-a]pyridine-7-carboxylic 190 acid dimethylamide AzetidineAzetidin-1-yl-imidazo[1,2-a]pyridine- 202 7-yl-methanone

Procedure A4—Iodination

To a solution of Imidazo[1,2-a]pyridine-7-carboxylic acid amide (1.0equiv) in DMF (280 ml) was added N-iodosuccinimide (1.2 equiv) and theresulting mixture was stirred for 2 h at room temperature. The thinbrown slurry was diluted with water, 10% w/v sodium thiosulfate andsodium carbonate (1M) and extracted with EtOAc. The aqueous was furtherextracted with EtOAc. The combined organic phases were washed with brine(280 ml), dried (MgSO₄) and concentrated in vacuo to give a brownresidue. The residue was triturated with ether, filtered and the solidwas washed with ether (2×50 ml) and dried on the filter to give theproduct. Where necessary the product was purified by chromatography onsilica (0→50% MeOH/Et₂O).

NRR′ Product MS: [M + H]⁺ NHMe 3-Iodoimidazo[1,2-a]pyridine-7-carboxylic302 acid methylamide NMe₂ 3-Iodoimidazo[1,2-a]pyridine-7-carboxylic 316acid dimethylamide

Azetidin-1-y1-(3-iodoimidazo[1,2-a] pyridine-7-yl)-methanone 328

Procedure A5b—Suzuki Coupling with3-([1,3,4]Thiadiazol-2-ylamino)-phenyl boronic acid pinacol ester

To a solution of 7-amido-3-iodo-imidazo[1,2-a]pyridine (1 equiv) in DMEwas added 3-([1,3,4]Thiadiazol-2-ylamino)-phenyl boronic acid pinacolester (1.2 equiv), 1M Na₂CO₃ (8 equiv) [reaction degassed by bubbling N₂through] followed by tetrakis(triphenylphosphine)palladium(0) (0.05equiv). The mixture was heated at 80° C. overnight, then diluted withwater and extracted with EtOAc. The organic layer was washed with brine,dried (MgSO₄) and concentrated under reduced pressure. The products werepurified by trituration with Et₂O or by column chromatography on silica(0→50% MeOH/Et₂O).

NRR′ Product   NHMe 3-[3-([1,3,4]-Thiadiazol-2-ylamino)-pheny1]-imidazo[1,2-a]pyridine-7-carboxylic acid methylamide NMe₂3-[3-([1,3,4]-Thiadiazol-2-ylamino)-pheny1]-imidazo[1,2-a]pyridine-7-carboxylic acid dimethylamide

Azetidin-1-yl-{3-[3-([1,3,4]thiadiazol-2-ylamino)-phenyl]-imidazo[1,2-a]pyridine-7-yl}-methanoneGeneral Route B

Procedure B1—Imidazo[1,2-a]pyridine-7-carboxylic acid amide

Prepared using general route A procedure A1, substituting2-aminoisonicotinamide for methyl 2-aminopyridine-4-carboxylate. 1H NMR(400 MHz, DMSO-d6): 8.59 (1H, d), 8.16 (1H, s), 8.13 (1H, s), 8.05 (1H,s), 7.71 (1H, s), 7.52 (1H, s), 7.32 (1H, dd). MS: [M+H]⁺162.

Procedure B2—3-Iodoimidazo[1,2-a]pyridine-7-carboxylic acid amide

Prepared using general route A procedure A4, substitutingImidazo[1,2-a]pyridine-7-carboxylic acid amide for methylimidazo[1,2-a]pyridine-7-carboxylate. 1H NMR (400 MHz, DMSO-d6): 8.39(1H, d), 8.25-8.09 (3H, m), 7.86 (1H, s), 7.56-7.45 (1H, dd). MS:[M+H]⁺288.

Procedure B3—Suzuki Coupling

3-Iodoimidazo[1,2-a]pyridine-7-carboxylic acid amide was coupled asdescribed in general route A, procedure A5.

Boronate Product

3-[3-([1,3,4]-Thiadiazol-2-ylamino)- phenyl]-imidazo[1,2-a]pyridine-7-carboxylic acid amide

EXAMPLES 1 TO 4

By following the methods described above, the compounds of Examples 1 to4 set out in the Table below were prepared.

Example Number Structure Name Method NMR Data MS Data 1

3-[3- ([1,3,4]Thiadiazol-2- ylamino)-phenyl]- imidazo[1,2- a]pyridine-7-carboxylic acid dimethylamide Hydrochloride General Route A 1H NMR (400MHz, Me-d3- OD): 8.80 (1 H, s), 8.63 (1 H, d), 8.05 (1 H, s), 7.78 (1 H,s), 7.70 (1 H, s), 7.55 (1 H, d), 7.48 (1 H, t), 7.27 (1 H, d), 7.04 (1H, d), 3.13 (6 H, s). [M + H] + 365 2

Azetidin-1-yl-{3-[3- ([1,3,4]thiadiazol-2- ylamino)-phenyl]-imidazo[1,2- a]pyridine-7-yl}- methanone General Route A 1H NMR (400MHz, DMSO-d6): 10.63 (1 H, s), 8.98-8.91 (1 H, m), 8.64 (1 H, d),8.04-7.97 (1 H, m), 7.97-7.92 (1 H, m), 7.90 (1 H, s), 7.71 (1 H, d),7.61-7.50 (1 H, m), 7.32 (1 H, d), 7.24-7.13 (1 H, m), 4.47 (2 H, s),4.10 (2 H, d), 3.43 (2 H, s), 2.37-2.25 (2 H, m). [M + H] + 377 3

3-[3-([1,3,4]- Thiadiazol-2- ylamino)-phenyl]- imidazo[1,2-a]pyridine-7- carboxylic acid amide General Route B 1H NMR (400 MHz,DMSO-d6): 8.68 (1 H, s), 8.64 (1 H, d), 8.26 (1 H, s), 8.20 (1 H, s),7.90 (2 H, s), 7.56 (2 H, d), 7.51-7.38 (3 H, m), 7.17 (1 H, d). [M +H] + 337 4

3-[3-([1,3,4]- Thiadiazol-2- ylamino)-phenyl]- imidazo[1,2-a]pyridine-7- carboxylic acid methylamide General Route A 1H NMR (400MHz, DMSO-d6): 8.93-8.85 (1 H, m), 8.72-8.62 (1 H, m), 8.20 (1 H, s),8.03-7.95 (1 H, m), 7.92 (1 H, s), 7.67 (1 H, d), 7.57-7.51 (1 H, m),7.41 (1 H, dd), 7.29 (1 H, d), 3.30 (1 H, s), 2.88-2.79 (3 H, m). [M +H] + 351Biological AssaysFGFR3 and PDGFR In Vitro Kinase Inhibitory Activity Assays

Enzymes (from Upstate) were prepared at 2× final concentration in 1×kinase assay buffer (as described below). Enzymes were then incubatedwith test compounds, biotinylated Flt3 substrate (biotin -DNEYFYV) (CellSignalling Technology Inc.) and ATP. The reaction was allowed to proceedfor 3 hours (FGFR3) or 2.5 hrs (PDGFR-beta) at room temperature on aplate shaker at 900 rpm before being stopped with 20 μl of 35 mM EDTA,pH 8 (FGFR3) or 55 mM EDTA, pH 8 (PDGFR-beta). Twenty μl of 5× detectionmix (50 mM HEPES pH 7.5, 0.1% BSA, 2 nM Eu-anti-pY (PY20) (PerkinElmer)15 nM SA-XL665 (Cisbio) for FGFR3 and 50 mM HEPES, pH 7.5, 0.5 M KF,0.1% BSA, 11.34 nM Eu-anti-pY (PT66) (PerkinElmer), 94 nM SA-XL665(Cisbio) for PDGFR-beta) was then added to each well and the platesealed and incubated at room temperature for one hour on a plate shakerat 900 rpm. The plate was then read on a Packard Fusion plate reader inTRF mode.

Flt3 substrate Enzyme 1 × Assay Buffer concentration ATP concentrationFGFR3 A 0.125 μM  8 μM PDGFR-beta B  0.15 μM 30 μM Kinase Assay bufferswere: A: 50 mM HEPES pH 7.5, 6 mM MnCl_(2,) 1 mM DTT, 0.1% TritonX-100B: 20 mM MOPS pH 7.0, 10 mM MnCl_(2,) 0.01% Triton X-100, 1 mM DTT, 0.1mM Sodium orthovanadate

Compounds of the invention have IC50 values less than 10 μM or provideat least 50% inhibition of the FGFR3 activity at a concentration of 10μM. Preferred compounds of the invention (for example Examples 1-4) haveIC50 values of less than 1 μM in the FGFR3 assay.

VEGFR2 In Vitro Kinase Inhibitory Activity Assay

Assay reactions containing VEGFR2 enzyme (purchased from Upstate), and250 μM Poly (Glu, Tyr) 4:1 substrate (CisBio) in 50 mM HEPES, pH 7.5, 6mM MnCl2, 1 mM DTT, 0.01% TritonX-100, 5 μM ATP (2.8 Ci/mmol) were setup in the presence of compound. Reactions were stopped after 15 minutesby adding an excess of phosphoric acid. The reaction mixture was thentransferred to a Millipore MAPH filter plate where the peptide binds andthe unused ATP is washed away. After washing, scintillant was added andthe incorporated activity measured by scintillation counting on aPackard Topcount.

FGFR1, FGFR2, FGFR4, VEGFR1 and VEGFR3 In Vitro Kinase InhibitoryActivity Assays

The inhibitory activity against FGFR1, FGFR2, FGFR4, VEGFR1 and VEGFR3can be determined at Upstate Discovery Ltd. Enzymes were prepared at 10×final concentration in enzyme buffer (20 mM MOPS, pH 7.0, 1 mM EDTA,0.1% B-mercaptoethanol, 0.01% Brij-35, 5% glycerol, 1 mg/ml BSA).Enzymes were then incubated in assay buffer with various substrates and³³P-ATP (˜500 cpm/pmol) as described in the table.

The reaction was initiated by the addition of Mg/ATP. The reaction wasallowed to proceed for 40 minutes at room temperature before beingstopped with 5 μl of a 3% phosphoric acid solution. Ten μl of thereaction mix was transferred to either a filtermat A or P30 filtermatand washed three times in 75 mM phosphoric acid and once in methanolbefore being dried for scintillation counting.

Compounds were tested at the concentrations detailed below in duplicateagainst all kinases and the percent activity compared to control wascalculated. Where inhibition was high an IC₅₀ was determined.

ATP Assay Concentration Enzyme Buffer Substrate (μM) FGFR1 A 250 μMKKKSPGEYVNIEFG 200 μM FGFR2 B 0.1 mg/ml poly(Glu, Tyr) 4:1  90 μM FGFR4C 0.1 mg/ml poly(Glu, Tyr) 4:1 155 μM VEGFR1 A 250 μM KKKSPGEYVNIEFG 200μM VEGFR3 A 500 μM GGEEEEYFELVKKKK 200 μM Enzyme buffer A: 8 mM MOPS, pH7.0, 0.2 mM EDTA, 10 mM MgAcetate Enzyme buffer B: 8 mM MOPS, pH 7.0,0.2 mM EDTA, 2.5 mM MnCl2, 10 mM MgAcetate Enzyme buffer C: 8 mM Mops,pH 7.0, 0.2 mM EDTA, 10 mM MnCl2, 10 mM MgAcetate.Cell-based pERK ELISA Method

LP-1 or JIM-1 multiple myeloma cells were seeded in 96 well plates at1×10⁶ cells/ml in 200 μl per well in serum free media. HUVEC cells wereseeded at 2.5×10⁵ cells/ml and allowed to recover for 24 h prior totransfer to serum free media. Cells were incubated for 16 h at 37° C.prior to the addition of a test compound for 30 minutes. Test compoundswere administered at a 0.1% final DMSO concentration. Following this 30minute incubation a FGF-1/Heparin (FGF-1 at 100 ng/ml final and Heparinat 100 ug/ml) mixture or VEGF¹⁶⁵ (100 ug/ml) was added to each of thewells for a further 5 minutes. The media was removed and 50 ul ERK ELISAlysis buffer (R and D Systems DuoSet ELISA for pERK and Total ERK #DYC-1940E, DYC-1018E) added. ELISA plates and standards were preparedaccording to the standard DuoSet protocols and the relative amounts ofpERK to total ERK in each sample calculated according to the standardcurve.

In particular, compounds of the invention were tested against the LP-1cell line (DSMZ no.: ACC 41) derived from human multiple myeloma. Manycompounds of the invention were found to have IC50 values of less than20 μM in this assay and some compounds (for example Example 2) has IC50values of less than 1 μM.

HUVEC Cell Based Selectivity Assays

HUVEC cells were seeded in 6 well plates at 1×10⁶ cells/well and allowedto recover for 24 h. They were transferred to serum free media for 16hours prior to treatment with test compound for 30 minutes in 0.1% DMSOfinal. Following compound incubation FGF-1 (100 ng/ml) and Heparin (100ug/ml) or VEGF¹⁶⁵ (100 ng/ml) were added for 5 minutes. Media wasremoved, cells washed with ice-cold PBS and lysed in 100 ul TG lysisbuffer (20 mM Tris, 130 nM NaCl, 1% Triton-X-100, 10% Glycerol, proteaseand phosphatase inhibitors, pH 7.5). Samples containing equivalentamounts of protein were made up with LDS sample buffer and run on SDSPAGE followed by western blotting for a number of downstream VEGFR andFGFR pathway targets including phospho-FGFR3, phospho-VEGFR2 andphospho-ERK1/2.

In vivo Models of Hypertension

A number of animal models exist to measure the potential hypertensiveeffects of small molecule inhibitors. They can be classified into twomain types; indirect and direct measurements. The most common indirectmethod is the cuff technique. Such methods have the advantages of beingnon-invasive and as such can be applied to a larger group ofexperimental animals however the process allows only intermittentsampling of blood pressure and requires the animal to be restrained insome way. Application of restraint can stress the animal and means thatchanges in blood pressure attributable to a specific drug effect can behard to pick up.

Direct methodologies include those that make use of radio telemetrytechnology or via indwelling catheters connected to externally mountedtransducers. Such methods require a high level of technical expertisefor the initial surgery involved in implantation and costs involved arehigh. However a key advantage is that they allow continuous monitoringof blood pressure without restraint over the time period of theexperiment. These methods are reviewed in Kurz et al (2005)Hypertension. 45: 299-310.

hERG Activity

The activity of compound of formula (I) against the hERG K⁺ ion channelcan be determined using the assay described in the article by M. H.Bridgland-Taylor et al., Journal of Pharmacological and ToxicologicalMethods, 54 (2006), 189-199. This IonWorks™ HT hERG screening assay isperformed commercially by Upstate (Millipore) using the PreciSiON™hERG-CHO cell line.

Determination of Potency Against Cytochrome P450

The potency of the compound of formula (I) against cytochrome P450(CYP450) enzymes 1A2, 2C9, 2C19, 3A4 and 2D6 can be determined using thePan Vera Vivid CYP450 screening kits available from Invitrogen (Paisley,UK). The CYP450s are supplied in the form of baculosomes containing theCYP450 and NADPH reductase and the substrates used are the fluorescentVivid substrates. The final reaction mixtures are as follows:

1A2

100 mM potassium phosphate, pH 8, 1% acetonitrile, 2 μM 1A2 Blue vividsubstrate, 100 μM NADP⁺, 4 nM CYP450 1A2, 2.66 mM glucose-6-phosphate,0.32 U/ml glucose-6-phosphate dehydrogenase.

2C9

50 mM potassium phosphate, pH 8, 1% acetonitrile, 2 μM Green vividsubstrate, 100 μM NADP⁺, 8 nM CYP450 2C9, 2.66 mM glucose-6-phosphate,0.32 U/ml glucose-6-phosphate dehydrogenase.

2C19

50 mM potassium phosphate, pH 8, 1% acetonitrile, 8 μM Blue vividsubstrate, 100 μM NADP⁺, 4 nM CYP450 2C19, 2.66 mM glucose-6-phosphate,0.32 U/ml glucose-6-phosphate dehydrogenase.

3A4

100 mM potassium phosphate, pH 8, 1% acetonitrile, 10 μM 3A4 Blue vividsubstrate, 100 μM NADP⁺, 2.5 nM CYP450 3A4, 2.66 mM glucose-6-phosphate,0.32 U/ml glucose-6-phosphate dehydrogenase.

2D6

100 mM potassium phosphate, pH 8, 1% acetonitrile, 5 μM 2D6 Blue vividsubstrate, 100 μM NADP⁺, 16 nM CYP450 2D6, 2.66 mM glucose-6-phosphate,0.32 U/ml glucose-6-phosphate dehydrogenase.

Fluorescence is monitored for 20 minutes at 30 second intervals on aMolecular Devices Gemini fluorescence plate reader. The excitation andemission wavelengths are 390 nm and 460 nm for 1A2, 2C19 and 3A4, 390 nmand 485 nm for 2D6 and 485 nm and 530 nm for 2C9. Initial rates aredetermined from progress curves.

The test compound is made up in methanol or acetonitrile and testedagainst the CYP450s at a concentration of 10 μM.

Ba/F3-TEL-FGFR3 & Ba/F3 (WT) Cell Proliferation Assays

Stably transfected Ba/F3-TEL-FGFR3 cells were plated out into black96-well tissue culture plates with clear bottoms in RPMI mediumcontaining 10% FBS and 0.25 mg/ml G418 at a density of 5×10³ cells/well(200 μl per well). The parental wild-type Ba/F3 cells (DSMZ no.: ACC300) were plated out into black 96-well tissue culture plates with clearbottoms in RPMI medium containing 10% FBS and 2 ng/ml mouse IL-3 (R&DSystems) at a density of 2.5×10³ cells/well (200 μl per well). Plateswere placed in an incubator overnight before adding the compounds thefollowing day. Dilutions of compounds were made in DMSO starting at 10mM and were diluted into the wells to give a final DMSO concentration of0.1% in assay. Compounds were left on the cells for 72 hours before theplates were removed from the incubator and 20 μl of Alamar Blue™(Biosource) was added to each well. Plates were placed in the incubatorfor 4-6 hours before reading plates at 535 nm (excitation)/590 nm(emission) on a Fusion plate reader (Packard).

Many compounds of the invention are expected to be more active againstBa/F3-TEL-FGFR3 cell line than the parental wild-type Ba/F3 cell line,for example over 5-fold, in particular 10 fold more active againstBa/F3-TEL-FGFR3 cell line than the parental wild-type Ba/F3 cell line.

1. A compound of formula (I):

wherein

represents a single or double bond, such that at least one bond withinthe 5 membered ring system is a double bond; Ring A may be optionallysubstituted by 1, 2 or 3 R^(a) groups; B represents a —V-carbocyclicgroup or a —W-heterocyclyl group wherein said carbocyclic andheterocyclyl groups may be optionally substituted by 1, 2 or 3 R^(a)groups; R^(e) and R^(f) independently represent hydrogen or C₁₋₆ alkyl;R^(a) represents halogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈cycloalkyl, C₃₋₈ cycloalkenyl, —OR^(x), —O—(CH₂)_(n)—OR^(x), haloC₁₋₆alkyl, haloC₁₋₆ alkoxy, C₁₋₆ alkanol, ═O, ═S, nitro, Si(R^(x))₄,—(CH₂)_(s)—CN, —S—R^(x), —SO—R^(x), —SO₂—R^(x), —COR^(x),—(CR^(x)R^(y))_(s)—COOR^(z), —(CH₂)_(s)—CONR^(x)R^(y),—(CH₂)_(s)—NR^(x)R^(y), —(CH₂)_(s)—NR^(x)COR^(y),—(CH₂)_(s)—NR^(x)SO₂—R^(y), —(CH₂)_(s)—NH—SO₂—NR^(x)R^(y),—OCONR^(x)R^(y), —(CH₂)_(s)—NR^(x)CO₂R^(y),—O—(CH₂)_(s)—CR^(x)R^(y)—(CH₂)_(t)—OR^(z) or —(CH₂)_(s)—SO₂NR^(x)R^(y)groups; R^(x), R^(y) and R^(z) independently represent hydrogen, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkanol, hydroxy, C₁₋₆ alkoxy,haloC₁₋₆ alkyl, —CO—(CH₂)_(n)—C₁₋₆ alkoxy, C₃₋₈ cycloalkyl or C₃₋₈cycloalkenyl; R⁷ and R⁸ independently represent hydrogen, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, aryl,heterocyclyl or R⁷ and R⁸ together with the nitrogen atom to which theyare attached may form a nitrogen containing heterocyclyl ring, whereinsaid C₁₋₆ alkyl, aryl and heterocyclyl may be optionally substituted by1, 2 or 3 R^(b) groups; R¹ and R^(b) independently represent an R^(a)group or a —Y-carbocyclic or —Z-heterocyclyl group wherein saidcarbocyclic and heterocyclyl groups may be optionally substituted by 1,2 or 3 R^(a) groups; V and W independently represent a bond or a—(CR^(e)R^(f))_(n)—group; Y and Z independently represent a bond,—CO—(CH₂)_(s)—, —COO—, —(CH₂)_(n)—, —NR^(x)—(CH₂)_(s)—,—(CH₂)_(s)—NR^(x)—, —CONR^(x)—, —NR^(x)CO—, —SO₂NR^(x)—, —NR^(x)SO₂—,—NR^(x)CONR^(y)—, —NR^(x)CSNR^(y)—, —O—(CH₂)_(s)—, —(CH₂)_(s)—O—, S—,—SO— or —(CH₂)_(s)—SO₂—; n represents an integer from 1-4; s and tindependently represent an integer from 0-4; q represents an integerfrom 0-2; or a pharmaceutically acceptable salt thereof.
 2. A compoundas defined in claim 1, wherein B represents an aromatic or non-aromaticheterocyclic group; R^(a) represents halogen, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, —OR^(x),—O—(CH₂)_(n)—OR^(x), haloC₁₋₆ alkyl, haloC₁₋₆ alkoxy, C₁₋₆ alkanol, ═O,═S, nitro, —(CH₂)_(s)—CN, —S—R^(x), —SO—R^(x), —SO₂—R^(x), —COR^(x),—(CR^(x)R^(y))_(s)—COOR^(z), —(CH₂)_(s)—CONR^(x)R^(y),—(CH₂)_(s)—NR^(x)R^(y), —(CH₂)_(s)—NR^(x)COR^(y),—(CH₂)_(s)—NR^(x)SO₂—R^(y), —OCONR^(x)R^(y), —(CH₂)_(s)—NR^(x)CO₂R^(y),—O—(CH₂)_(s)—CR^(x)R^(y)—(CH₂)_(t)—OR^(z) or —(CH₂)_(s)—SO₂NR^(x)R^(Y)groups; and Y and Z independently represent a bond, —CO—, —CH₂—,—(CH₂)₂, —(CH₂)₃—, —O—(CH₂)_(s),— or —NH—(CH₂)_(n)—.
 3. A compound asdefined in claims 1 wherein B represents a —W-heterocyclyl group.
 4. Acompound as defined in claim 3 wherein W represents a bond.
 5. Acompound as defined in claim 3 wherein the heterocyclyl group is a 5 or6 membered monocyclic heterocyclyl group.
 6. A compound as defined inclaim 5 wherein the heterocyclyl group is pyridyl, pyrazinyl, triazolyl,oxadiazolyl, imidazolyl or thiadiazolyl.
 7. A compound as defined inclaim 1 wherein q represents
 0. 8. A compound as defined in claim 1wherein R⁷ and R⁸ both represent hydrogen or C₁₋₆ alkyl; or one of R⁷and R⁸ represents hydrogen and the other represents C₁₋₆ alkyl(optionally substituted by an —OR^(x) group), C₃₋₈ cycloalkyl orheterocyclyl.
 9. A compound as defined in claim 1 wherein R⁷ and R⁸together with the nitrogen atom to which they are attached form anitrogen containing heterocyclyl ring optionally substituted by 1, 2 or3 R^(b) groups.
 10. A compound as defined in claim 1 having thefollowing ring system:


11. A pharmaceutical composition comprising a compound of formula (I) asdefined in claim
 1. 12. A process for the preparation of a compound offormula (I) as defined in claim 1, which process comprises: (i) thereaction of a compound of the formula (II):

or a protected form thereof, with an appropriately substituted aldehydeor ketone; or (ii) the reaction of a compound of the formula (II):

or a protected form thereof, with hydrazine hydrate and then cyclising;or (iii) the reaction of a compound of the formula (III):

or a protected form thereof, wherein Y is a groups which can beconverted to an amide, and then converting to an amide; and thereafterremoving any protecting group present; and optionally thereafterconverting one compound of the formula (I) into another compound of theformula (I).